Researchers Database

karasawa tadayoshi

    DivisionofInflammationResearch Assistant Professor
Last Updated :2021/11/23

Researcher Information

URL

J-Global ID

Research Areas

  • Life sciences / Metabolism and endocrinology

Published Papers

  • Ayae Ozeki, Yuka Oogaki, Yuka Henmi, Tadayoshi Karasawa, Masafumi Takahashi, Hironori Takahashi, Akihide Ohkuchi, Koumei Shirasuna
    Journal of hypertension 2021/08 
    OBJECTIVES: Maternal systemic and placental inflammatory responses participate in the pathogenesis of hypertensive disorders of pregnancy including preeclampsia, a pregnancy-specific syndrome, although the role of inflammation remains unclear. The NLRP3 inflammasome has been implicated in the control of sterile inflammation involved in preeclampsia. In the present study, we hypothesized that S100A9, as major alarmin, are associated with the pathogenesis of preeclampsia and induction of a preeclampsia-like phenotype in pregnant mice. METHODS: Plasma were taken from normal pregnant women and preeclampsia patients. Human placental tissues, trophoblast cell line Sw.71 cells, and human umbilical vein endothelial cells (HUVEC) were treated with S100A9 with or without inhibitors associated with NLRP3 inflammasome. Pregnant mice were administered S100A9. RESULTS: S100A9 was elevated in plasma and released from placentas of preeclampsia patients. S100A9 activated the NLRP3 inflammasome, resulting in IL-1β secretion, by human placental tissues and trophoblasts. In addition, secretion of soluble endoglin, a main contributor to the pathogenesis of preeclampsia, is regulated via S100A9-stimulated NLRP3 inflammasome activation in the human placenta and HUVECs. S100A9 administration significantly elevated maternal blood pressure and neutrophil accumulation within the placentas of pregnant mice, and both were significantly decreased in Nlrp3-knock out pregnant mice. CONCLUSION: The results of this study demonstrated that S100A9 acts as a danger signal to activate the NLRP3 inflammasome in the placenta, associating with hypertension during pregnancy.
  • Sachiko Watanabe, Fumitake Usui-Kawanishi, Takanori Komada, Tadayoshi Karasawa, Ryo Kamata, Naoya Yamada, Hiroaki Kimura, Katsuya Dezaki, Tsukasa Ohmori, Masafumi Takahashi
    Biochemical and biophysical research communications 531 (2) 125 - 132 2020/10 
    BACKGROUND: Platelets are critical mediators of vascular homeostasis and thrombosis, and also contribute to the development of inflammation. NLRP3 inflammasome is a cytosolic multi-protein complex that consists of NLRP3, ASC and caspase-1, and regulates IL-1β-mediated inflammation. METHOD AND RESULTS: Using two mouse models of thrombosis (i.e., occlusion of the middle cerebral artery and inferior vena cava), we found that thrombus formation was significantly enhanced in ASC-deficient (ASC-/-) mice, compared to that in wild-type (WT) and IL-1β-/- mice. ASC deficiency had no effects on blood coagulation parameters (i.e., prothrombin time [PT] and activated partial thromboplastin time [APTT]). Platelets from WT mice express ASC, but neither NLRP3 nor caspase-1. ASC deficiency significantly enhanced the expression of P-selectin and GPIIb/IIIa in response to a GPVI agonist (collagen-related peptide [CRP]), but not to thrombin, in platelets. CRP induced ASC speck formation in WT platelets. ASC deficiency also enhanced cytosolic Ca2+ elevation and phosphorylation of ERK1/2 and Akt in platelets. CONCLUSION: Our results demonstrate that ASC negatively regulates GPVI signaling in platelets and enhances thrombus formation, independent of NLRP3 inflammasome and IL-1β, and provide novel insights into the link between inflammation and thrombosis.
  • Homare Ito, Hiroaki Kimura, Tadayoshi Karasawa, Shu Hisata, Ai Sadatomo, Yoshiyuki Inoue, Naoya Yamada, Emi Aizawa, Erika Hishida, Ryo Kamata, Takanori Komada, Sachiko Watanabe, Tadashi Kasahara, Takuji Suzuki, Hisanaga Horie, Joji Kitayama, Naohiro Sata, Kazuyo Yamaji-Kegan, Masafumi Takahashi
    Journal of immunology (Baltimore, Md. : 1950) 2020/07 [Refereed][Not invited]
     
    Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1β, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1β prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1β is a novel potential target for treating and preventing this disorder.
  • Michiya Sano, Sayaka Shimazaki, Yasuaki Kaneko, Tadayoshi Karasawa, Masafumi Takahashi, Akihide Ohkuchi, Hironori Takahashi, Akira Kurosawa, Yasushi Torii, Hisataka Iwata, Takehito Kuwayama, Koumei Shirasuna
    The Journal of reproduction and development 66 (3) 241 - 248 2020/06 
    Maternal obesity is one of the major risk factors for pregnancy complications and is associated with low-grade chronic systemic inflammation due to higher levels of pro-inflammatory cytokines such as interleukin (IL)-1β. Pregnant women with obesity have abnormal lipid profiles, characterized by higher levels of free fatty acids, especially palmitic acid (PA). Previously, we reported that PA stimulated IL-1β secretion via activation of NLRP3 inflammasome in human placental cells. These observations led us to hypothesize that higher levels of PA induce NLRP3 inflammasome activation and placental inflammation, resulting in pregnancy complications. However, the effects of PA on NLRP3 inflammasome during pregnancy in vivo remain unclear. Therefore, PA solutions were administered intravenously into pregnant mice on day 12 of gestation. Maternal body weight was significantly decreased and absorption rates were significantly higher in PA-injected mice. The administration of PA significantly increased IL-1β protein and the mRNA expression of NLRP3 inflammasome components (NLRP3, ASC, and caspase-1) within the placenta. In murine placental cell culture, PA significantly stimulated IL-1β secretion, and this secretion was suppressed by a specific NLRP3 inhibitor (MCC950). Simultaneously, the number of macrophages/monocytes and neutrophils, together with the mRNA expression of these chemokines increased significantly in the placentas of PA-treated mice. Treatment with PA induced ASC assembling and IL-1β secretion in macrophages, and this PA-induced IL-1β secretion was significantly suppressed in NLRP3-knockdown macrophages. These results indicate that transient higher levels of PA exposure in pregnant mice activates NLRP3 inflammasome and induces placental inflammation, resulting in the incidence of absorption.
  • Emi Aizawa, Tadayoshi Karasawa, Sachiko Watanabe, Takanori Komada, Hiroaki Kimura, Ryo Kamata, Homare Ito, Erika Hishida, Naoya Yamada, Tadashi Kasahara, Yoshiyuki Mori, Masafumi Takahashi
    iScience 23 (5) 101070 - 101070 2020/05 
    Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1β release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1β forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.
  • Sachiko Watanabe, Fumitake Usui‐Kawanishi, Tadayoshi Karasawa, Hiroaki Kimura, Ryo Kamata, Takanori Komada, Yoshiyuki Inoue, Nathan Mise, Tadashi Kasahara, Masafumi Takahashi
    Journal of Cellular Physiology 2020/03 [Refereed][Not invited]
  • Naoya Yamada, Tadayoshi Karasawa, Hiroaki Kimura, Sachiko Watanabe, Takanori Komada, Ryo Kamata, Ariunaa Sampilvanjil, Junya Ito, Kiyotaka Nakagawa, Hiroshi Kuwata, Shuntaro Hara, Koichi Mizuta, Yasunaru Sakuma, Naohiro Sata, Masafumi Takahashi
    Cell Death & Disease 2020/02 [Refereed][Not invited]
  • Ariunaa Sampilvanjil, Tadayoshi Karasawa, Naoya Yamada, Takanori Komada, Tsunehito Higashi, Chintogtokh Baatarjav, Sachiko Watanabe, Ryo Kamata, Nobuhiko Ohno, Masafumi Takahashi
    American journal of physiology. Heart and circulatory physiology 318 (3) H508-H518  2020/01 [Refereed][Not invited]
     
    Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in VSMCs. CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors (Ferrostatin-1 [Fer-1] and Liproxstatin-1) and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (N-acetyl cysteine) and NADPH oxidase inhibitor (DPI), but not by inhibitors of pan-caspases (Z-VAD), caspase-1 (Z-YVAD), or necroptosis (Necrostatin-1). CSE also upregulated IL-1β, IL-6, TNF-α, MMP-2, MMP-9, and TIMP-1 in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.
  • Yamada N, Karasawa T, Wakiya T, Sadatomo A, Ito H, Kamata R, Watanabe S, Komada T, Kimura H, Sanada Y, Sakuma Y, Mizuta K, Ohno N, Sata N, Takahashi M
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20 (6) 1606 - 1618 1600-6135 2020/01 [Refereed][Not invited]
     
    Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron-dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited hepatic I/R-induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury.
  • 川崎病疾患モデルにおけるNLRP3インフラマソームの役割
    安齋 文弥, 渡邊 幸子, 木村 博昭, 鎌田 諒, 唐澤 直義, 駒田 敬則, 竹石 恭知, 高橋 将文
    Anti-aging Science (株)メディカルレビュー社 11 (1) 61 - 61 1884-3891 2019/12 [Refereed][Not invited]
  • Anzai F, Watanabe S, Kimura H, Kamata R, Karasawa T, Komada T, Nakamura J, Nagi-Miura N, Ohno N, Takeishi Y, Takahashi M
    Journal of molecular and cellular cardiology 138 185 - 196 2019/12 [Refereed][Not invited]
     
    Kawasaki disease (KD) is a systemic febrile syndrome during childhood that is characterized by coronary arteritis. The etiopathogenesis of KD remains to be elucidated. NLRP3 inflammasome is a large multiprotein complex that plays a key role in IL-1β-driven sterile inflammatory diseases. In the present study, we investigated the role of NLRP3 inflammasome in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS) and found that NLRP3 inflammasome is required for the development of CAWS-induced vasculitis. CAWS administration induced IL-1β production, caspase-1 activation, leukocyte infiltration, and fibrotic changes in the aortic root and coronary arteries, which were significantly inhibited by a deficiency of IL-1β, NLRP3, and ASC. In vitro experiments showed that among cardiac resident cells, macrophages, but not endothelial cells or fibroblasts, expressed Dectin-2, but did not produce IL-1β in response to CAWS. In contrast, CAWS induced caspase-1 activation and IL-1β production in bone marrow-derived dendritic cells (BMDCs), which were inhibited by a specific caspase-1 inhibitor and a deficiency of NLRP3, ASC, and caspase-1. CAWS induced NLRP3 and pro-IL-1β expression through a Dectin-2/Syk/JNK/NF-κB pathway, and caspase-1 activation and cleavage of pro-IL-1β through Dectin-2/Syk/JNK-mediated mitochondrial ROS generation, indicating that CAWS induces the priming and activation of NLRP3 inflammasome in BMDCs. These findings provide new insights into the pathogenesis of KD vasculitis, and suggest that NLRP3 inflammasome may be a potential therapeutic target for KD.
  • Homare Ito, Ai Sadatomo, Yoshiyuki Inoue, Naoya Yamada, Emi Aizawa, Erika Hishida, Ryo Kamata, Tadayoshi Karasawa, Hiroaki Kimura, Sachiko Watanabe, Takanori Komada, Hisanaga Horie, Joji Kitayama, Naohiro Sata, Masafumi Takahashi
    Biochemical and biophysical research communications 519 (1) 15 - 22 0006-291X 2019/10 [Refereed][Not invited]
     
    BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. However, the underlying mechanism is not yet fully understood. Toll-like receptor 5 (TLR5) is highly expressed in mucosa and recognizes flagellin, the main component of the bacterial flagella. Here, we investigated the role of TLR5 in inflammation and tissue damage after intestinal I/R injury using TLR5-deficient mice. METHODS AND RESULTS: Intestinal levels of TLR5 mRNA and flagellin protein were elevated in wild-type mice subjected to intestinal I/R. Although TLR5 deficiency had no effect on intestinal flagellin levels, it significantly attenuated intestinal injury and inflammatory responses after intestinal I/R. TLR5 deficiency also markedly improved survival in mice after intestinal I/R injury. In wild-type mice, intestinal I/R injury induced remote organ damage, particularly in the lung, which was attenuated by TLR5 deficiency. Furthermore, TLR5 deficiency prevented lung inflammatory responses and vascular permeability after intestinal I/R injury. CONCLUSION: These findings demonstrate a novel role of TLR5 and provide new insights into the mechanism underlying inflammation and tissue damage after intestinal I/R injury.
  • Mizushina Y, Karasawa T, Aizawa K, Kimura H, Watanabe S, Kamata R, Komada T, Mato N, Kasahara T, Koyama S, Bando M, Hagiwara K, Takahashi M
    Journal of immunology (Baltimore, Md. : 1950) 203 (1) 236 - 246 0022-1767 2019/07 [Refereed][Not invited]
     
    Inflammation plays a pivotal role in the pathophysiology of gastric aspiration-induced acute lung injury (ALI). However, its mechanism remains unclear. In this study, we investigated the role of NLRP3 inflammasome-driven IL-1β production in a mouse model of acid aspiration-induced inflammation and ALI. Acid aspiration-induced inflammatory responses and ALI in wild-type mice were significantly attenuated in IL-1β-/- mice, but not NLRP3-/- mice. In vitro experiments revealed that severe acidic stress (pH 1.75) induced the processing of pro-IL-1β into its 18-kDa mature form (p18-IL-1β), which was different from the caspase-1-processed 17-kDa form (p17-IL-1β), in human THP-1 macrophages and primary murine macrophages. Deficiency of NLRP3 and caspase-1 had no effect on acidic stress-produced IL-1β. The production of IL-1β by severe acidic stress was prevented by inhibitors of serine proteases [4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride], but not of cysteine proteases (E-64), cathepsin G, or inflammasome. The cathepsin D inhibitor pepstatin A inhibited IL-1β production induced by mild acidic stress (pH 6.2) or lactic acid, but not severe acidic stress. Using mass spectrometry and processing-site mutants of pro-IL-1β, we identified D109 as a novel cleavage site of pro-IL-1β in response to severe acidic stress and calculated the theoretical molecular mass of the mature form to be 18.2 kDa. The bioactivity of acidic stress-produced IL-1β was confirmed by its ability to promote p38 phosphorylation and chemokine upregulation in alveolar epithelial cells. These findings demonstrate a novel mechanism of acid-induced IL-1β production and inflammation independent of NLRP3 inflammasome and provide new insights into the therapeutic strategies for aspiration pneumonitis and ALI.
  • Hishida E, Ito H, Komada T, Karasawa T, Kimura H, Watanabe S, Kamata R, Aizawa E, Kasahara T, Morishita Y, Akimoto T, Nagata D, Takahashi M
    Scientific reports 9 (1) 10363 - 10363 2019/07 [Refereed][Not invited]
     
    Long-term peritoneal dialysis (PD) therapy leads to peritoneal inflammation and fibrosis. However, the mechanism underlying PD-related peritoneal inflammation and fibrosis remains unclear. NLRP3 inflammasome regulates the caspase-1-dependent release of interleukin-1β and mediates inflammation in various diseases. Here, we investigated the role of NLRP3 inflammasome in a murine model of PD-related peritoneal fibrosis induced by methylglyoxal (MGO). Inflammasome-related proteins were upregulated in the peritoneum of MGO-treated mice. MGO induced parietal and visceral peritoneal fibrosis in wild-type mice, which was significantly reduced in mice deficient in NLRP3, ASC, and interleukin-1β (IL-1β). ASC deficiency reduced the expression of inflammatory cytokines and fibrotic factors, and the infiltration of macrophages. However, myeloid cell-specific ASC deficiency failed to inhibit MGO-induced peritoneal fibrosis. MGO caused hemorrhagic ascites, fibrin deposition, and plasminogen activator inhibitor-1 upregulation, but all of these manifestations were inhibited by ASC deficiency. Furthermore, in vitro experiments showed that MGO induced cell death via the generation of reactive oxygen species in vascular endothelial cells, which was inhibited by ASC deficiency. Our results showed that endothelial NLRP3 inflammasome contributes to PD-related peritoneal inflammation and fibrosis, and provide new insights into the mechanisms underlying the pathogenesis of this disorder.
  • Shirasuna K, Karasawa T, Takahashi M
    Journal of cellular physiology 234 (5) 5436 - 5450 0021-9541 2019/05 [Refereed][Not invited]
  • Karasawa T, Takahashi M
    Aging 11 (6) 1613 - 1614 2019/03 [Refereed][Not invited]
  • Jun Nakamura, Sachiko Watanabe, Hiroaki Kimura, Motoi Kobayashi, Tadayoshi Karasawa, Ryo Kamata, Fumitake Usui-Kawanishi, Ai Sadatomo, Hiroaki Mizukami, Noriko Nagi-Miura, Naohito Ohno, Tadashi Kasahara, Seiji Minota, Masafumi Takahashi
    Scientific Reports 8 (1) 7601  2045-2322 2018/12 [Refereed][Not invited]
     
    Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD.
  • Wakabayashi T, Takahashi M, Yamamuro D, Karasawa T, Takei A, Takei S, Yamazaki H, Nagashima S, Ebihara K, Takahashi M, Ishibashi S
    Arteriosclerosis, thrombosis, and vascular biology 38 (11) 2576 - 2589 1079-5642 2018/11 [Refereed][Not invited]
  • Sakai K, Nagashima S, Wakabayashi T, Tumenbayar B, Hayakawa H, Hayakawa M, Karasawa T, Ohashi K, Yamazaki H, Takei A, Takei S, Yamamuro D, Takahashi M, Yagyu H, Osuga JI, Takahashi M, Tominaga SI, Ishibashi S
    Arteriosclerosis, thrombosis, and vascular biology 38 (11) 2590 - 2600 1079-5642 2018/11 [Refereed][Not invited]
     
    Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m-/m-) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane-associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.
  • E3ユビキチンリガーゼARIH2によるNLRP3インフラマソーム制御機構の解明
    鎌田 諒, 川島 晃, 唐澤 直義, 渡邊 幸子, 木村 博昭, 高橋 将文
    脈管学 (一社)日本脈管学会 58 (Suppl.) S152 - S152 0387-1126 2018/09 [Refereed][Not invited]
  • Yamada N, Katano T, Hirata Y, Okada N, Sanada Y, Ihara Y, Urahashi T, Ushijima K, Karasawa T, Takahashi M, Mizuta K
    Journal of gastroenterology and hepatology 34 (2) 418 - 424 0815-9319 2018/08 [Refereed][Not invited]
     
    BACKGROUND AND AIM: Serum Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel fibrosis marker for various chronic liver diseases. We investigated the ability of M2BPGi to predict liver fibrosis in liver transplant (LT) recipients. METHODS: A total of 116 liver biopsies were performed in 113 LT recipients. The serum level of M2BPGi was also measured on the same day. The median age at LT and liver biopsy was 1.1 and 11.8 years, respectively. Serum M2BPGi levels and liver fibrosis status using METAVIR fibrosis score were compared. Immunohistological evaluation by anti-α-smooth-muscle actin (αSMA) was performed, and the relationship between αSMA positive rate and serum M2BPGi levels was investigated. RESULTS: The median M2BPGi level was 0.78 (range, 0.22-9.50), and 65, 29, 16, 5, and 1 patient(s) had METAVIR fibrosis scores of F0, F1, F2, F3, and F4, respectively. In patients with F0 fibrosis, median M2BPGi level was 0.69 and was significantly lower than in patients with F1 (median 0.99, P < 0.01), F2 (median 1.00, P = 0.01), and F3 fibrosis (median 1.53, P < 0.01). Area-under-the-curve analysis of the ability of M2BPGi level to predict liver fibrosis grade were > F1: 0.716, > F2: 0.720, and > F3: 0.900. Three patients with acute cellular rejection showed high levels of M2BPGi, which decreased after the treatment. A positive correlation existed between M2BPGi levels and αSMA positive rate (r2  = 0.715, P < 0.01). CONCLUSION: Mac-2 binding protein glycosylation isomer is a novel liver fibrosis marker in LT recipients and is also increased in patients with acute liver injuries, especially acute cellular rejection, even when fibrosis is absent.
  • Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages
    Karasawa, Tadayoshi, Kawashima, Akira, Usui-Kawanishi, Fumitake, Watanabe, Sachiko, Kimura, Hiroaki, Kamata, Ryo, Shirasuna, Koumei, Koyama, Yutaro, Sato-Tomita, Ayana, Matsuzaka, Takashi, Tomoda, Hiroshi, Park, Sam-Yong, Shibayama, Naoya, Shimano, Hitoshi, Kasahara, Tadashi, Takahashi, Masafumi
    Arteriosclerosis, thrombosis, and vascular biology LIPPINCOTT WILLIAMS & WILKINS 1524-4636 2018/04 [Not refereed][Not invited]
  • Tadayoshi Karasawa, Akira Kawashima, Fumitake Usui-Kawanishi, Sachiko Watanabe, Hiroaki Kimura, Ryo Kamata, Koumei Shirasuna, Yutaro Koyama, Ayana Sato-Tomita, Takashi Matsuzaka, Hiroshi Tomoda, Sam-Yong Park, Naoya Shibayama, Hitoshi Shimano, Tadashi Kasahara, Masafumi Takahashi
    Arteriosclerosis, Thrombosis, and Vascular Biology 38 (4) 744 - 756 1524-4636 2018/04 [Refereed][Not invited]
     
    Objective - Inflammation provoked by the imbalance of fatty acid composition, such as excess saturated fatty acids (SFAs), is implicated in the development of metabolic diseases. Recent investigations suggest the possible role of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3) inflammasome, which regulates IL-1β (interleukin 1β) release and leads to inflammation, in this process. Therefore, we investigated the underlying mechanism by which SFAs trigger NLRP3 inflammasome activation. Approach and Results - The treatment with SFAs, such as palmitic acid and stearic acid, promoted IL-1β release in murine primary macrophages while treatment with oleic acid inhibited SFA-induced IL-1β release in a dose-dependent manner. Analyses using polarized light microscopy revealed that intracellular crystallization was provoked in SFA-treated macrophages. As well as IL-1β release, the intracellular crystallization and lysosomal dysfunction were inhibited in the presence of oleic acid. These results suggest that SFAs activate NLRP3 inflammasome through intracellular crystallization. Indeed, SFA-derived crystals activated NLRP3 inflammasome and subsequent IL-1β release via lysosomal dysfunction. Excess SFAs also induced crystallization and IL-1β release in vivo. Furthermore, SFA-derived crystals provoked acute inflammation, which was impaired in IL-1β-deficient mice. Conclusions - These findings demonstrate that excess SFAs cause intracellular crystallization and subsequent lysosomal dysfunction, leading to the activation of the NLRP3 inflammasome, and provide novel insights into the pathogenesis of metabolic diseases.
  • Ai Sadatomo, Yoshiyuki Inoue, Homare Ito, Tadayoshi Karasawa, Hiroaki Kimura, Sachiko Watanabe, Yoshiko Mizushina, Jun Nakamura, Ryo Kamata, Tadashi Kasahara, Hisanaga Horie, Naohiro Sata, Masafumi Takahashi
    JOURNAL OF IMMUNOLOGY 199 (9) 3306 - 3315 0022-1767 2017/11 [Refereed][Not invited]
     
    Accumulating evidence suggests that IL-1 beta plays a pivotal role in the pathophysiology of hepatic ischemia-reperfusion (I/R) injury; however, the mechanism by which I/R triggers IL-1 beta production in the liver remains unclear. Recent data have shown that neutrophils contribute to hepatic I/R injury independently of the inflammasomes regulating IL-1 beta maturation. Thus, we investigated the role of neutrophils in IL-1 beta maturation and tissue injury in a murine model of hepatic I/R. IL-1 beta was released from the I/R liver and its deficiency reduced reactive oxygen species generation, apoptosis, and inflammatory responses, such as inflammatory cell infiltration and cytokine expression, thereby resulting in reduced tissue injury. Depletion of either macrophages or neutrophils also attenuated IL-1 beta release and hepatic I/R injury. In vitro experiments revealed that neutrophil-derived proteinases process pro-IL-1 beta derived from macrophages into its mature form independently of caspase-1. Furthermore, pharmacological inhibition of serine proteases attenuated IL-1 beta release and hepatic I/R injury in vivo. Taken together, the interaction between neutrophils and macrophages promotes IL-1 beta maturation and causes IL-1 beta-driven inflammation in the I/R liver. Both neutrophils and macrophages are indispensable in this process. These findings suggest that neutrophil-macrophage interaction is a therapeutic target for hepatic I/R injury and may also provide new insights into the inflammasome-independent mechanism of IL-1 beta maturation in the liver.
  • Akira Kawashima, Tadayoshi Karasawa, Kenji Tago, Hiroaki Kimura, Ryo Kamata, Fumitake Usui-Kawanishi, Sachiko Watanabe, Satoshi Ohta, Megumi Funakoshi-Tago, Ken Yanagisawa, Tadashi Kasahara, Koichi Suzuki, Masafumi Takahashi
    JOURNAL OF IMMUNOLOGY 199 (10) 3614 - 3622 0022-1767 2017/11 [Refereed][Not invited]
     
    The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a molecular platform that induces caspase-1 activation and subsequent IL-1b maturation, and is implicated in inflammatory diseases; however, little is known about the negative regulation of NLRP3 inflammasome activation. In this article, we identified an E3 ligase, Ariadne homolog 2 (ARIH2), as a posttranslational negative regulator of NLRP3 inflammasome activity in macrophages. ARIH2 interacted with NLRP3 via its NACHT domain (aa 220-575) in the NLRP3 inflammasome complex. In particular, we found that while using mutants of ARIH2 and ubiquitin, the really interesting new gene 2 domain of ARIH2 was required for NLRP3 ubiquitination linked through K48 and K63. Deletion of endogenous ARIH2 using CRISPR/Cas9 genome editing inhibited NLRP3 ubiquitination and promoted NLRP3 inflammasome activation, resulting in apoptosis-associated speck-like protein containing a caspase recruitment domain oligomerization, pro-IL-1b processing, and IL-1b production. Conversely, ARIH2 overexpression promoted NLRP3 ubiquitination and inhibited NLRP3 inflammasome activation. Our findings reveal a novel mechanism of ubiquitination-dependent negative regulation of the NLRP3 inflammasome by ARIH2 and highlight ARIH2 as a potential therapeutic target for inflammatory diseases.
  • Motoi Kobayashi, Fumitake Usui-Kawanishi, Tadayoshi Karasawa, Hiroaki Kimura, Sachiko Watanabe, Nathan Mise, Fujio Kayama, Tadashi Kasahara, Naoyuki Hasebe, Masafumi Takahashi
    PLOS ONE 12 (5) e0176676  1932-6203 2017/05 [Refereed][Not invited]
     
    Cardiac glycosides such as digoxin are Na+/K+ -ATPase inhibitors that are widely used for the treatment of chronic heart failure and cardiac arrhythmias; however, recent epidemiological studies have suggested a relationship between digoxin treatment and increased mortality. We previously showed that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, which regulate caspase-1-dependent interleukin (IL)-1 beta release, mediate the sterile cardiovascular inflammation. Because the Na+/K+ -ATPase is involved in inflammatory responses, we investigated the role of NLRP3 inflammasomes in the pathophysiology of cardiac glycoside-induced cardiac inflammation and dysfunction. The cardiac glycoside ouabain induced cardiac dysfunction and injury in wild-type mice primed with a low dose of lipopolysaccharide (LPS), although no cardiac dysfunction was observed in mice treated with either ouabain or LPS alone. Ouabain also induced cardiac inflammatory responses, such as macrophage infiltration and IL-d1 beta release, when mice were primed with LPS. These cardiac manifestations were all significantly attenuated in mice deficient in IL-1 beta. Furthermore, deficiency of NLRP3 inflammasome components, NLRP3 and caspase-1, also attenuated ouabain-induced cardiac dysfunction and inflammation. In vitro experiments revealed that ouabain induced NLRP3 inflammasome activation as well as subsequent IL-1 beta release from macrophages, and this activation was mediated by K+ efflux. Our findings demonstrate that cardiac glycosides promote cardiac inflammation and dysfunction through NLRP3 inflammasomes and provide new insights into the mechanisms underlying the adverse effects of cardiac glycosides.
  • Tadayoshi Karasawa, Masafumi Takahashi
    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 24 (5) 443 - 451 1340-3478 2017 [Refereed][Not invited]
     
    Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1 beta, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.
  • Karasawa T, Takahashi M
    Inflammation and regeneration 37 18  1880-9693 2017 [Refereed][Not invited]
  • Kotomi Seno, Hirolci Takano, Ayaka Ohtsu, Akihide Ohkuchi, Tadayoshi Karasawa, Masafumi Takahashi, Hisataka Iwata, Takehito Kuwayama, Koumei Shirasuna
    JOURNAL OF REPRODUCTIVE IMMUNOLOGY 118 134 - 134 0165-0378 2016/11 [Refereed][Not invited]
  • Hiroaki Kimura, Tadayoshi Karasawa, Fumitake Usui, Akira Kawashima, Yuka Endo, Motoi Kobayashi, Ai Sadatomo, Jun Nakamura, Yusaku Iwasaki, Toshihiko Yada, Hiroko Tsutsui, Tadashi Kasahara, Masafumi Takahashi
    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 311 (5) E881 - E890 0193-1849 2016/11 [Refereed][Not invited]
     
    Caspase-1 is a cysteine protease responsible for the processing of the proinflammatory cytokine interleukin-1 beta and activated by the formation of inflammasome complexes. Although several investigations have found a link between diet-induced obesity and caspase-1, the relationship remains controversial. Here, we found that mice deficient in caspase-1 were susceptible to high-fat dietinduced obesity with increased adiposity as well as normal lipid and glucose metabolism. Caspase-1 deficiency clearly promoted the infiltration of inflammatory macrophages and increased the production of C-C motif chemokine ligand 2 (CCL2) in the adipose tissue. The dominant cellular source of CCL2 was stromal vascular fraction rather than adipocytes in the adipose tissue. These findings demonstrate a critical role of caspase-1 in macrophage-driven inflammation in the adipose tissue and the development of obesity. These data provide novel insights into the mechanisms underlying inflammation in the pathophysiology of obesity.
  • Koumei Shirasuna, Hiroki Takano, Kotomi Seno, Ayaka Ohtsu, Tadayoshi Karasawa, Masafumi Takahashi, Akihide Ohkuchi, Hirotada Suzuki, Shigeki Matsubara, Hisataka Iwata, Takehito Kuwayama
    JOURNAL OF REPRODUCTIVE IMMUNOLOGY 116 104 - 112 0165-0378 2016/08 [Refereed][Not invited]
     
    Maternal obesity, a major risk factor for adverse pregnancy complications, results in inflammatory cytokine release in the placenta. Levels of free fatty acids are elevated in the plasma of obese human. These fatty acids include obesity-related palmitic acids, which is a major saturated fatty acid, that promotes inflammatory responses. Increasing evidence indicates that nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasomes mediate inflammatory responses induced by endogenous danger signals. We hypothesized that inflammatory responses associated with gestational obesity cause inflammation. To test this hypothesis, we investigated the effect of palmitic acid on the activation of NLRP3 inflammasomes and inflammatory responses in a human Sw.71 trophoblast cell line. Palmitic acid stimulated caspase-1 activation and markedly increased interleukin (IL)-1 beta secretion in Sw.71 cells. Treatment with a caspase-1 inhibitor diminished palmitic acid-induced IL-1 beta release. In addition, NLRP3 and caspase-1 genome editing using a CRISPR/Cas9 system in Sw.71 cells suppressed IL-1 beta secretion, which was stimulated by palmitic acid. Moreover, palmitic acid stimulated caspase-3 activation and inflammatory cytokine secretion (e.g., IL-6 and IL-8). Palmitic acid-induced cytokine secretion were dependent on caspase-3 activation. In addition, palmitic acid-induced IL-1 beta, IL-6, and IL-8 secretion was depended on reactive oxygen species (ROS) generation. In conclusion, palmitic acid caused activation of NLRP3 inflammasomes and inflammatory responses, inducing IL-1 beta, IL-6, and IL-8 secretion, which is associated with ROS generation, in human Sw.71 placental cells. We suggest that obesity-related palmitic acid induces placental inflammation, resulting in association with pregnancy complications. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Motoi Kobayashi, Fumitake Usui, Tadayoshi Karasawa, Akira Kawashima, Hiroaki Kimura, Yoshiko Mizushina, Koumei Shirasuna, Hiroaki Mizukami, Tadashi Kasahara, Naoyuki Hasebe, Masafumi Takahashi
    SCIENTIFIC REPORTS 6 26489  2045-2322 2016/05 [Refereed][Not invited]
     
    NLRP3 inflammasomes recognize non-microbial danger signals and induce release of proinflammatory cytokine interleukin (IL)-1 beta, leading to sterile inflammation in cardiovascular disease. Because sterile inflammation is involved in doxorubicin (Dox)-induced cardiotoxicity, we investigated the role of NLRP3 inflammasomes in Dox-induced cardiotoxicity. Cardiac dysfunction and injury were induced by low-dose Dox (15 mg/kg) administration in NLRP3-deficient (NLRP3(-/-)) mice but not in wild-type (WT) and IL-1 beta(-/-) mice, indicating that NLRP3 deficiency enhanced the susceptibility to Dox-induced cardiotoxicity independent of IL-1 beta. Although the hearts of WT and NLRP3(-/-) mice showed no significant difference in inflammatory cell infiltration, macrophages were the predominant inflammatory cells in the hearts, and cardiac IL-10 production was decreased in Dox-treated NLRP3(-/-) mice. Bone marrow transplantation experiments showed that bone marrow-derived cells contributed to the exacerbation of Dox-induced cardiotoxicity in NLRP3(-/-) mice. In vitro experiments revealed that NLRP3 deficiency decreased IL-10 production in macrophages. Furthermore, adeno-associated virus-mediated IL-10 overexpression restored the exacerbation of cardiotoxicity in the NLRP3(-/-) mice. These results demonstrated that NLRP3 regulates macrophage IL-10 production and contributes to the pathophysiology of Dox-induced cardiotoxicity, which is independent of IL-1 beta. Our findings identify a novel role of NLRP3 and provided new insights into the mechanisms underlying Dox-induced cardiotoxicity.
  • Shirasuna Koumei, Karasawa Tadayoshi, Usui Fumitake, Kimura Hiroaki, Kawashima Akira, Ohkuchi Akihide, Iwata Hisataka, Kuwayama Takehito, Takahashi Masafumi
    JOURNAL OF REPRODUCTIVE IMMUNOLOGY 112 124 - 125 0165-0378 2015/11 [Refereed][Not invited]
  • Koumei Shirasuna, Tadayoshi Karasawa, Fumitake Usui, Motoi Kobayashi, Tadanori Komada, Hiroaki Kimura, Akira Kawashima, Akihide Ohkuchi, Shun'ichiro Taniguchi, Masafumi Takahashi
    ENDOCRINOLOGY 156 (11) 4281 - 4292 0013-7227 2015/11 [Refereed][Not invited]
     
    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.
  • Amna Abderrazak, Dominique Couchie, Dler Faieeq Darweesh Mahmood, Rima Elhage, Cecile Vindis, Muriel Laffargue, Veronique Mateo, Berthold Buechele, Monica Rubio Ayala, Menna El Gaafary, Tatiana Syrovets, Mohamed-Naceur Slimane, Bertrand Friguet, Tamas Fulop, Thomas Simmet, Khadija El Hadri, Mustapha Rouis
    CIRCULATION 132 (21) e250 - e251 0009-7322 2015/11 [Refereed][Not invited]
  • Hiroaki Kimura, Fumitake Usui, Tadayoshi Karasawa, Akira Kawashima, Koumei Shirasuna, Yoshiyuki Inoue, Takanori Komada, Motoi Kobayashi, Yoshiko Mizushina, Tadashi Kasahara, Koichi Suzuki, Yusaku Iwasaki, Toshihiko Yada, Patrizio Caturegli, Masafumi Takahashi
    SCIENTIFIC REPORTS 5 15883  2045-2322 2015/10 [Refereed][Not invited]
     
    Inflammation plays an important role in the development of obesity and metabolic disorders; however, it has not been fully understood how inflammation occurs and is regulated in their pathogenesis. Low-molecular mass protein-7 (LMP7) is a proteolytic subunit of the immunoproteasome that shapes the repertoire of antigenic peptides on major histocompatibility complex class I molecule. In this study, we investigated the role of LMP7 in the development of obesity and metabolic disorders using LMP7-deficient mice. LMP7 deficiency conveyed resistant to obesity, and improved glucose intolerance and insulin sensitivity in mice fed with high-fat diet (HFD). LMP7 deficiency decreased pancreatic lipase expression, increased fecal lipid contents, and inhibited the increase of plasma triglyceride levels upon oral oil administration or HFD feeding. Using bone marrow-transferred chimeric mice, we found that LMP7 in both bone marrow-and non-bone marrow-derived cells contributes to the development of HFD-induced obesity. LMP7 deficiency decreased inflammatory responses such as macrophage infiltration and chemokine expression while it increased serum adiponection levels. These findings demonstrate a novel role for LMP7 and provide new insights into the mechanisms underlying inflammation in the pathophysiology of obesity and metabolic disorders.
  • Shirasuna K, Usui F, Karasawa T, Kimura H, Kawashima A, Mizukami H, Ohkuchi A, Nishimura S, Sagara J, Noda T, Ozawa K, Taniguchi S, Takahashi M
    Nanotoxicology 2015 (9) 554 - 567 1743-5404 2015/09 [Refereed][Not invited]
  • Takanori Komada, Fumitake Usui, Akira Kawashima, Hiroaki Kimura, Tadayoshi Karasawa, Yoshiyuki Inoue, Motoi Kobayashi, Yoshiko Mizushina, Tadashi Kasahara, Shun'ichiro Taniguchi, Shigeaki Muto, Daisuke Nagata, Masafumi Takahashi
    SCIENTIFIC REPORTS 5 10901  2045-2322 2015/06 [Refereed][Not invited]
     
    Rhabdomyolysis is one of the main causes of community-acquired acute kidney injury (AKI). Although inflammation is involved in the pathogenesis of rhabdomyolysis-induced AKI (RIAKI), little is known about the mechanism that triggers inflammation during RIAKI. Recent evidence has indicated that sterile inflammation triggered by tissue injury can be mediated through multiprotein complexes called the inflammasomes. Therefore, we investigated the role of NLRP3 inflammasomes in the pathogenesis of RIAKI using a glycerol-induced murine rhabdomyolysis model. Inflammasomerelated molecules were upregulated in the kidney of RIAKI. Renal tubular injury and dysfunction preceded leukocyte infiltration into the kidney during the early phase of RIAKI, and they were markedly attenuated in mice deficient in NLRP3, ASC, caspase-1, and interleukin (IL)-1 beta compared with those in wild-type mice. No difference in leukocyte infiltration was observed between wild-type and NLRP3-deficient mice. Furthermore, NLRP3 deficiency strikingly suppressed the expression of renal injury markers and inflammatory cytokines and apoptosis of renal tubular cells. These results demonstrated that NLRP3 inflammasomes contribute to inflammation, apoptosis, and tissue injury during the early phase of RIAKI and provide new insights into the mechanism underlying the pathogenesis of RIAKI.
  • Tadayoshi Karasawa, Masafumi Takahashi
    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 81 136 - 138 0022-2828 2015/04 [Refereed][Not invited]
  • Yoshiko Mizushina, Koumei Shirasuna, Fumitake Usui, Tadayoshi Karasawa, Akira Kawashima, Hiroaki Kimura, Motoi Kobayashi, Takanori Komada, Yoshiyuki Inoue, Naoko Mato, Hideaki Yamasawa, Eicke Latz, Yoichiro Iwakura, Tadashi Kasahara, Masashi Bando, Yukihiko Sugiyama, Masafumi Takahashi
    JOURNAL OF BIOLOGICAL CHEMISTRY 290 (8) 5065 - 5077 0021-9258 2015/02 [Refereed][Not invited]
     
    Supplemental oxygen inhalation is frequently used to treat severe respiratory failure; however, prolonged exposure to hyperoxia causes hyperoxic acute lung injury (HALI), which induces acute respiratory distress syndrome and leads to high mortality rates. Recent investigations suggest the possible role of NLRP3 inflammasomes, which regulate IL-1 beta production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In this study, we investigated the role of NLRP3 inflammasomes in mice with HALI. Under hyperoxic conditions, NLRP3(-/-) mice died at a higher rate compared with wild-type and IL-1 beta(-/-) mice, and there was no difference in IL-1 beta production in their lungs. Under hyperoxic conditions, the lungs of NLRP3(-/-) mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, as well as increased and decreased expression of MMP-9 and Bcl-2, respectively. NLRP3(-/-) mice exhibited diminished expression and activation of Stat3, which regulatesMMP-9 and Bcl-2, in addition to increased numbers of apoptotic alveolar epithelial cells. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils and chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independent of IL-1 beta production and contributes to the pathophysiology of HALI.
  • Tadayoshi Karasawa, Akira Kawashima, Fumitake Usui, Hiroaki Kimura, Koumei Shirasuna, Yoshiyuki Inoue, Takanori Komada, Motoi Kobayashi, Yoshiko Mizushina, Junji Sagara, Masafumi Takahashi
    FEBS OPEN BIO 5 348 - 356 2211-5463 2015 [Refereed][Not invited]
     
    Increasing evidence indicates that caspase recruitment domain (CARD)-mediated caspase-1 (CASP1) assembly is an essential process for its activation and subsequent interleukin (IL)-1 beta release, leading to the initiation of inflammation. Both CARD16 and CARD17 were previously reported as inhibitory homologs of CASP1; however, their molecular function remains unclear. Here, we identified that oligomerization activity allows CARD16 to function as a CASP1 activator. We investigated the molecular characteristics of CARD16 and CARD17 in transiently transfected HeLa cells. Although both CARD16 and CARD17 interacted with CASP1CARD, only CARD16 formed a homo-oligomer. Oligomerized CARD16 formed a filament-like structure with CASP1CARD and a speck with apoptosis-associated speck-like protein containing a CARD. A filament-like structure formed by CARD16 promoted CASP1 filament assembly and IL-1 beta release. In contrast, CARD17 did not form a homo-oligomer or filaments and inhibited CASP1-dependent IL-1 beta release. Mutated CARD16(D27G), mimicking the CARD17 amino acid sequence, formed a homo-oligomer but failed to form a filament-like structure. Consequently, CARD16D27G weakly promoted CASP1 filament assembly and subsequent IL-1 beta release. These results suggest that oligomerized CARD16 promotes CARD-mediated molecular assembly and CASP1 activation. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. This is an open access article under the CC BY-NC-ND license.
  • Koumei Shirasuna, Fumitake Usui, Tadayoshi Karasawa, Hiroaki Kimura, Akira Kawashima, Hiroaki Mizukami, Akihide Ohkuchi, Satoshi Nishimura, Junji Sagara, Tetsuo Noda, Keiya Ozawa, Shun'ichiro Taniguchi, Masafumi Takahashi
    NANOTOXICOLOGY 9 (5) 554 - 567 1743-5390 2015 [Refereed][Not invited]
     
    Despite the increasing commercial use of nanoparticles, little is known about their effects on placental inflammation and pregnancy complications. In this study, nanosilica (NS) particles upregulated the inflammasome component nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) and induced placental inflammation and reactive oxygen species (ROS) generation, resulting in pregnancy complications. Furthermore, NS-induced pregnancy complications were markedly improved in N mice but not in component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-deficient (Asc) mice, indicating the independence of NLRP3 inflammasomes. Pregnancy complications in Nlrp3(-/-) and Asc(-/-) mice phenotypes were dependent on the balance between interleukin (IL)-1 a and IL-10. NS-induced pregnancy complications were completely prevented by either inhibition of ROS generation or forced expression of IL-10. Our findings provide important information about NS-induced placental inflammation and pregnancy complications and the novel pathophysiological roles of NLRP3 and ASC in pregnancy.
  • Fumitake Usui, Koumei Shirasuna, Hiroaki Kimura, Kazuki Tatsumi, Akira Kawashima, Tadayoshi Karasawa, Koichi Yoshimura, Hiroki Aoki, Hiroko Tsutsui, Tetsuo Noda, Junji Sagara, Shun'ichiro Taniguchi, Masafumi Takahashi
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 35 (1) 127 - 136 1079-5642 2015/01 [Refereed][Not invited]
     
    Objective-Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA remains unclear. We previously showed that the inflammasome, which regulates the caspase-1-dependent interleukin-1 beta production, mediates the sterile cardiovascular inflammatory responses. Therefore, we hypothesized that the inflammasome is a key mediator of initial inflammation in AAA formation. Approach and Results-Apoptosis-associated speck-like protein containing a caspase recruitment domain is highly expressed in adventitial macrophages in human and murine AAA tissues. Using an established mouse model of AAA induced by continuous infusion of angiotensin II in Apoe(-/-) mice, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe(-/-) mice were shown to decrease the incidence, maximal diameter, and severity of AAA along with adventitial fibrosis and inflammatory responses significantly, such as inflammatory cell infiltration and cytokine expression in the vessel wall. NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency in Apoe(-/-) mice also reduced elastic lamina degradation and metalloproteinase activation in the early phase of AAA formation. Furthermore, angiotensin II stimulated generation of mitochondria-derived reactive oxygen species in the adventitial macrophages, and this mitochondria-derived reactive oxygen species generation was inhibited by NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1 deficiency. In vitro experiments revealed that angiotensin II stimulated the NLRP3 inflammasome activation and subsequent interleukin-1 beta release in macrophages, and this activation was mediated through an angiotensin type I receptor/mitochondria-derived reactive oxygen species-dependent pathway. Conclusions-Our results demonstrate the importance of the NLRP3 inflammasome in the initial inflammatory responses in AAA formation, indicating its potential as a novel therapeutic target for preventing AAA progression.
  • Yoshimi Nakagawa, Aoi Satoh, Sachiko Yabe, Mika Furusawa, Naoko Tokushige, Hitomi Tezuka, Motoki Mikami, Wakiko Iwata, Akiko Shingyouchi, Takashi Matsuzaka, Shiori Kiwata, Yuri Fujimoto, Hidehisa Shimizu, Hirosuke Danno, Takashi Yamamoto, Kiyoaki Ishii, Tadayoshi Karasawa, Yoshinori Takeuchi, Hitoshi Iwasaki, Masako Shimada, Yasushi Kawakami, Osamu Urayama, Hirohito Sone, Kazuhiro Takekoshi, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Naoya Yahagi, Hiroaki Suzuki, Nobuhiro Yamada, Hitoshi Shimano
    ENDOCRINOLOGY 155 (12) 4706 - 4719 0013-7227 2014/12 [Refereed][Not invited]
     
    Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor(PPAR) alpha promoter in an autoloop fashion and is crucial for the ligand transactivation of PPAR alpha by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1 alpha. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.
  • Kyoko Hara, Koumei Shirasuna, Fumitake Usul, Tadayoshi Karasawa, Yoshiko Mizushina, Hiroaki Kimura, Akira Kawashima, Akihide Ohkuchi, Shuichi Matsuyama, Koji Kimura, Masafumi Takahashi
    PLOS ONE 9 (12) e113974  1932-6203 2014/12 [Refereed][Not invited]
     
    Background: Type I interferons (IFNs), including IFN-alpha (IFNA) and IFN-beta (IFNB), have anti-inflammatory properties and are used to treat patients with autoimmune and inflammatory disorders. However, little is known of the role of IFN-tau (IFNT), a type I IFN produced by ruminant animals for inflammation. Because IFNB has recently been shown to inhibit nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome activation and subsequent secretion of the potent inflammatory cytokine interleukin (IL)-1 beta, we examined the effects of ruminant IFNT on NLRP3 inflammasome-mediated IL-1 beta secretion in human THP-1 macrophages. Methods and Results: IFNT dose-dependently inhibited IL-1 beta secretion induced by nano-silica, a well-known activators of NLRP3 inflammasomes, in human macrophages primed with lipopolysaccharide (LPS, TLR4 agonist) and Pam3CSK4 (TLR1/2 agonist). IFNT also suppressed phagocytosis of nano-silica and reactive oxygen species (ROS) generation. Western blot analysis showed that IFNT inhibited both pro-IL-1 beta and mature IL-1 beta. In addition, real-time RT-PCR analysis showed that IFNT suppressed IL-1 beta mRNA expression induced by LPS and Pam3CSK4. Although nano-silica particles did not induce IL-10 secretion, IFNT induced IL-10 secretion in a dose-dependent manner. Furthermore, IFNT-suppressed IL-1 beta secretion was restored by anti-IL-10 neutralizing antibody. Conclusions: Ruminant IFNT inhibits NLRP3 inflammasome-driven IL-1 beta secretion in human macrophages via multiple pathways, including the uptake of nano-silica particles, generation of ROS, and IL-10-mediated inhibition of pro-IL-1 beta induction. It may be a therapeutic alternative to IFNA and IFNB.
  • Yoshiyuki Inoue, Koumei Shirasuna, Hiroaki Kimura, Fumitake Usui, Akira Kawashima, Tadayoshi Karasawa, Kenji Tago, Katsuya Dezaki, Satoshi Nishimura, Junji Sagara, Tetsuo Noda, Yoichiro Iwakura, Hiroko Tsutsui, Shun'ichiro Taniguchi, Ken Yanagisawa, Toshihiko Yada, Yoshikazu Yasuda, Masafumi Takahashi
    JOURNAL OF IMMUNOLOGY 192 (9) 4342 - 4351 0022-1767 2014/05 [Refereed][Not invited]
     
    Inflammation plays a key role in the pathophysiology of hepatic ischemia-reperfusion (I/R) injury. However, the mechanism by which hepatic I/R induces inflammatory responses remains unclear. Recent evidence indicates that a sterile inflammatory response triggered by I/R is mediated through a multiple-protein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in hepatic I/R injury and found that hepatic I/R stimuli upregulated the inflammasome-component molecule, nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), but not apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). NLRP3(-/-) mice, but not ASC(-/-) and caspase-1(-/-) mice, had significantly less liver injury after hepatic I/R. NLRP3(-/-) mice showed reduced inflammatory responses, reactive oxygen species production, and apoptosis in I/R liver. Notably, infiltration of neutrophils, but not macrophages, was markedly inhibited in the I/R liver of NLRP3(-/-) mice. Bone marrow transplantation experiments showed that NLRP3 not only in bone marrow-derived cells, but also in non-bone marrow-derived cells contributed to liver injury after I/R. In vitro experiments revealed that keratinocyte-derived chemokine-induced activation of heterotrimeric G proteins was markedly diminished. Furthermore, NLRP3(-/-) neutrophils decreased keratinocyte-derived chemokine-induced concentrations of intracellular calcium elevation, Rac activation, and actin assembly formation, thereby resulting in impaired migration activity. Taken together, NLRP3 regulates chemokine-mediated functions and recruitment of neutrophils, and thereby contributes to hepatic I/R injury independently of inflammasomes. These findings identify a novel role of NLRP3 in the pathophysiology of hepatic I/R injury.
  • Takanori Komada, Fumitake Usui, Koumei Shirasuna, Akira Kawashima, Hiroaki Kimura, Tadayoshi Karasawa, Satoshi Nishimura, Junji Sagara, Tetsuo Noda, Shun'ichiro Taniguchi, Shigeaki Muto, Daisuke Nagata, Eiji Kusano, Masafumi Takahashi
    AMERICAN JOURNAL OF PATHOLOGY 184 (5) 1287 - 1298 0002-9440 2014/05 [Refereed][Not invited]
     
    Inflammation plays a crucial role in the pathophysiologicat characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a muttiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X(7)-potassium efflux and reactive oxygen species dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.
  • Fumitake Usui, Koumei Shirasuna, Hiroaki Kimura, Kazuki Tatsumi, Akira Kawashima, Tadayoshi Karasawa, Shigeaki Hida, Junji Sagara, Shun'ichiro Taniguchi, Masafumi Takahashi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 425 (2) 162 - 168 0006-291X 2012/08 [Refereed][Not invited]
     
    Objective: Recent investigations have suggested that the inflammasome plays a role in the development of vascular inflammation and atherosclerosis; however, its precise role remains controversial. We produced double-deficient mice for apolipoprotien E (Apoe) and caspase-1 (Casp1), a key component molecule of the inflammasome, and investigated the effect of caspase-1 deficiency on vascular inflammation and atherosclerosis. Methods and results: Atherosclerotic plaque areas in whole aortas and aortic root of Western diet (WD)-fed Apoe(-/-)Casp1(-/-) mice were significantly reduced compared to those in Apoe(-/-) mice. The amount of macrophages and vascular smooth muscle cells in the plaques was also reduced in Apoe(-/-)Casp1(-/-) mice. No significant differences in plasma lipid profiles and body weight change were observed between these mice. Expression of interleukin (IL)-1 beta in the plaques as well as plasma levels of IL-1 beta, IL-1 alpha, IL-6, CCL2, and TNF-alpha, in Apoe(-/-)Casp1(-/-) mice were lower than those in Apoe(-/-) mice. In vitro experiments showed that calcium phosphate crystals induced caspase-1 activation and secretion of IL-1 beta and IL-1 alpha, in macrophages. Conclusion: Our findings suggest that caspase-1 plays a critical role in vascular inflammation and atherosclerosis, and that modulation of caspase-1 could be a potential target for prevention and treatment of atherosclerosis. (c) 2012 Elsevier Inc. All rights reserved.
  • Shin Kumadaki, Tadayoshi Karasawa, Takashi Matsuzaka, Masatsugu Ema, Yoshimi Nakagawa, Masanori Nakakuki, Ryo Saito, Naoya Yahagi, Hitoshi Iwasaki, Hirohito Sone, Kazuhiro Takekoshi, Shigeru Yatoh, Kazuto Kobayashi, Akimitsu Takahashi, Hiroaki Suzuki, Satoru Takahashi, Nobuhiro Yamada, Hitoshi Shimano
    JOURNAL OF BIOLOGICAL CHEMISTRY 47 286 (47) 40835 - 40846 0021-9258 2011/11 [Refereed][Not invited]
     
    F-box and WD repeat domain-containing 7 alpha (Ebw7 alpha) is the substrate recognition component of a ubiquitin ligase that controls the degradation of factors involved in cellular growth, including c-Myc, cyclin E, and c-Jun. In addition, Fbw7 alpha degrades the nuclear form of sterol regulatory element-binding protein (SREBP)-1a, a global regulator of lipid synthesis, particularly during mitosis in cultured cells. This study investigated the in vivo role of Ebw7 alpha in hepatic lipid metabolism. siRNA knockdown of Ebw7 alpha in mice caused marked hepatosteatosis with the accumulation of triglycerides. However, inhibition of Ebw7 alpha did not change the level of nuclear SREBP-1 protein or the expression of genes involved in fatty acid synthesis and oxidation. In vivo experiments on the gain and loss of Fbw7 alpha function indicated that Fbw7 alpha regulated the expression of peroxisome proliferator-activated receptor (PPAR) gamma 2 and its target genes involved in fatty acid uptake and triglyceride synthesis. These genes included fatty acid transporter Cd36, diacylglycerol acyltransferase 1 (Dgatl), and fat-specific protein 27 (Cidec). The regulation of PPAR gamma 2 by Fbw7 alpha was mediated, at least in part, by the direct degradation of the Krtippel-like factor 5 (KI.F5) protein, upstream of PPAR gamma 2 expression. Hepatic Fbw7 alpha contributes to normal fatty acid and triglyceride metabolism, functions that represent novel aspects of this cell growth regulator.
  • Ryo Saito, Takashi Matsuzaka, Tadayoshi Karasawa, Motohiro Sekiya, Nazuki Okada, Masaki Igarashi, Rie Matsumori, Kiyoaki Ishii, Yoshimi Nakagawa, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Hirohito Sone, Hiroaki Suzuki, Naoya Yahagi, Nobuhiro Yamada, Hitoshi Shimano
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 31 (9) 1973 - U143 1079-5642 2011/09 [Refereed][Not invited]
     
    Objective-Elovl6, a long-chain fatty acid elongase, is a rate-limiting enzyme that elongates saturated and monounsaturated fatty acids and has been shown to be related to obesity-induced insulin resistance via modification of fatty acid composition. In this study, we investigated the roles of Elovl6 in foam cell formation in macrophages and atherosclerosis in mice. Methods and Results-To investigate the roles of Elovl6 in macrophages in the progression of atherosclerosis, we transplanted bone marrow cells of wild-type or Elovl6(-/-) mice into irradiated LDL-R(-/-) mice that were fed a western diet. Aortic atherosclerotic lesion areas and infiltration of macrophages were significantly smaller in Elovl6(-/-) bone marrow cells-transplanted LDL-R(-/-) mice than in wild-type. Accumulation of esterified cholesterol on exposure to acetylated-LDL was less severe in peritoneal macrophages from Elovl6(-/-) mice than those from wild-type. Cholesterol efflux and expression of cholesterol efflux transporters were increased in Elovl6(-/-) macrophages, although no difference in uptake of acetylated-LDL was found between the two groups. On analysis of fatty acid composition of the esterified cholesterol fraction in macrophages, n-6 polyunsaturated fatty acids were decreased by absence of Elovl6. Conclusion-These findings suggest that Elovl6 in macrophages may contribute to foam cell formation and progression of atherosclerosis. (Arterioscler Thromb Vasc Biol. 2011;31:1973-1979.)
  • Tadayoshi Karasawa, Akimitsu Takahashi, Ryo Saito, Motohiro Sekiya, Masaki Igarashi, Hitoshi Iwasaki, Shoko Miyahara, Saori Koyasu, Yoshimi Nakagawa, Kiyoaki Ishii, Takashi Matsuzaka, Kazuto Kobayashi, Naoya Yahagi, Kazuhiro Takekoshi, Hirohito Sone, Shigeru Yatoh, Hiroaki Suzuki, Nobuhiro Yamada, Hitoshi Shimano
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 31 (8) 1788 - U201 1079-5642 2011/08 [Refereed][Not invited]
     
    Objective-Sterol regulatory element-binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis. Methods and Results-Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)-deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet-induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively. Conclusion-Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles. (Arterioscler Thromb Vasc Biol. 2011;31:1788-1795.)
  • Takashi Matsuzaka, Hitoshi Shimano, Naoya Yahagi, Toyonori Kato, Ayaka Atsumi, Takashi Yamamoto, Noriyuki Inoue, Mayumi Ishikawa, Sumiyo Okada, Naomi Ishigaki, Hitoshi Iwasaki, Yuko Iwasaki, Tadayoshi Karasawa, Shin Kumadaki, Toshiyuki Matsui, Motohiro Sekiya, Ken Ohashi, Alyssa H. Hasty, Yoshimi Nakagawa, Akimitsu Takahashi, Hiroaki Suzuki, Sigeru Yatoh, Hirohito Sone, Hideo Toyoshima, Jun-ichi Osuga, Nobuhiro Yamada
    NATURE MEDICINE 13 (10) 1193 - 1202 1078-8956 2007/10 [Refereed][Not invited]
     
    Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high- fat diet or mated to leptin- deficient ob/ ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate- 2 and suppression of hepatic protein kinase C e activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.

MISC

  • 木村博昭, 木村博昭, 唐澤直義, 駒田敬則, 鎌田諒, 笠原忠, 高橋将文  日本薬学会九州支部大会講演要旨集  36th-  2019
  • Homare Ito, Yoshiyuki Inoue, Ai Sadatomo, Naoya Yamada, Ryo Kamata, Sachiko Watanabe, Tadayoshi Karasawa, Hiroaki Kimura, Yasunaru Sakuma, Hisanaga Horie, Yoshinori Hosoya, Joji Kitayama, Naohiro Sata, Masafumi Takahashi  GASTROENTEROLOGY  154-  (6)  S497  -S497  2018/05  
    0
  • CAWS誘導川崎病様マウス血管炎のIL-10による病態抑制効果
    木村 博昭, 中村 潤, 渡邊 幸子, 唐澤 直義, 鎌田 涼, 笠原 忠, 三浦 典子, 大野 尚仁, 高橋 将文  日本薬学会年会要旨集  138年会-  (4)  70  -70  2018/03  [Not refereed][Not invited]
  • 鎌田諒, 川島晃, 唐澤直義, 渡邊幸子, 木村博昭, 高橋将文  脈管学(Web)  58-  (supplement)  S152(J‐STAGE)  2018  [Not refereed][Not invited]
  • Kyoko Honne, Masahiro Iwamoto, Shunichiro Hanai, Satoshi Machida, Hitoshi Sekiya, Reina Tsuda, Tatsuhiko Ozawa, Tadayoshi Karasawa, Atsushi Muraguchi, Masafumi Takahashi, Hiroyuki Kishi, Seiji Minota  ARTHRITIS & RHEUMATOLOGY  69-  2017/10  [Not refereed][Not invited]
  • Hiroaki Kimura, Tadayoshi Karasawa, Sachiko Watanabe, Koichi Suzuki, Patrizio Caturegli, Masafumi Takahashi  JOURNAL OF IMMUNOLOGY  198-  (1)  2017/05  [Not refereed][Not invited]
  • ヒト絨毛細胞株(Sw71)においてパルミチン酸はNLRP3インフラマソームを活性化する
    妹尾 琴実, 鷹野 弘樹, 大津 彩華, 大口 昭英, 唐澤 直義, 高橋 将文, 岩田 尚孝, 桑山 岳人, 白砂 孔明  Reproductive Immunology and Biology  31-  (1-2)  135  -135  2016/11  [Not refereed][Not invited]
  • K. Shirasuna, F. Usui, T. Karasawa, H. Kimura, A. Kawashima, H. Mizukami, A. Ohkuchi, M. Takahashi  JOURNAL OF REPRODUCTIVE IMMUNOLOGY  106-  14  -14  2014/12  [Not refereed][Not invited]
  • Masafumi Takahashi, Fumitake Usui, Akira Kawashima, Tadayoshi Karasawa, Hiroaki Kimura  CIRCULATION  130-  2014/11  [Not refereed][Not invited]
  • ナノ粒子による妊娠機能異常の機序 自然炎症インフラマソーム機構の関与の可能性
    白砂 孔明, 臼井 文武, 唐澤 直義, 木村 博昭, 川島 晃, 水上 浩明, 大口 昭英, 高橋 将文  Reproductive Immunology and Biology  29-  (1-2)  84  -84  2014/11  [Not refereed][Not invited]
  • ナノ粒子は妊娠マウスの胎盤炎症と妊娠機能異常を引き起こす 自然炎症経路・インフラマソームの関与
    白砂 孔明, 臼井 文武, 唐澤 直義, 木村 博昭, 川島 晃, 大口 昭英, 高橋 将文  The Journal of Reproduction and Development  60-  (Suppl.)  j94  -j94  2014/08  [Not refereed][Not invited]
  • インターフェロン(IFN)τはナノ粒子の取り込みを阻害してインターロイキン(IL)-1β産生を抑制する
    原 教子, 白砂 孔明, 臼井 文武, 唐澤 直義, 木村 博昭, 川島 晃, 大口 昭英, 松山 秀一, 木村 康二, 高橋 将文  The Journal of Reproduction and Development  60-  (Suppl.)  j137  -j137  2014/08  [Not refereed][Not invited]
  • マクロファージ泡沫化および動脈硬化における脂肪酸伸長酵素Elovl6の役割
    松坂 賢, 齋藤 亮, 唐澤 直義, 松森 理恵, 煙山 紀子, 中川 嘉, 石井 清朗, 岩崎 仁, 小林 和人, 矢藤 繁, 高橋 昭光, 曽根 博仁, 鈴木 浩明, 矢作 直也, 山田 信博, 島野 仁  糖尿病  55-  (Suppl.1)  S  -312  2012/04  [Not refereed][Not invited]

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