分子病態治療研究センター 炎症・免疫研究部

駒田 敬則

Takanori Komada

基本情報

所属
自治医科大学 分子病態治療研究センター 炎症・免疫研究部 講師

J-GLOBAL ID
201901020340616185
researchmap会員ID
B000360017

論文

 47
  • Naoya Yamada, Tadayoshi Karasawa, Junya Ito, Daisuke Yamamuro, Kazushi Morimoto, Toshitaka Nakamura, Takanori Komada, Chintogtokh Baatarjav, Yuma Saimoto, Yuka Jinnouchi, Kazuhisa Watanabe, Kouichi Miura, Naoya Yahagi, Kiyotaka Nakagawa, Takayoshi Matsumura, Ken-Ichi Yamada, Shun Ishibashi, Naohiro Sata, Marcus Conrad, Masafumi Takahashi
    Nature communications 15(1) 2195-2195 2024年3月12日  
    Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
  • Tadayoshi Karasawa, Takanori Komada, Chintogtokh Baatarjav, Emi Aizawa, Yoshiko Mizushina, Kenta Fujimura, Yoshitaka Gunji, Satoko Komori, Hidetoshi Aizawa, Cantona Billton Jing Tao, Takayoshi Matsumura, Masafumi Takahashi
    Biochemical and biophysical research communications 686 149158-149158 2023年12月17日  
    Caspase-11 is an inflammatory caspase that triggers an inflammatory response by regulating non-canonical NLRP3 inflammasome activation. Although the deficiency of both caspase-11 and caspase-1, another inflammatory caspase that functions as an executor of the inflammasome, prevents the development of atherosclerosis, the effect of caspase-11 deficiency alone on the development of atherosclerosis has not been fully evaluated. In the present study, we found that caspase-11 deficiency prevented the formation of the necrotic core, whereas it did not affect the development of atherosclerosis in Apoe-deficient mice. Notably, the infiltration of neutrophils into atherosclerotic lesions was attenuated by caspase-11 deficiency. RNA-seq analysis of stage-dependent expression of atherosclerotic lesions revealed that both upregulations of caspase-11 and neutrophil migration are common features of advanced atherosclerotic lesions. Furthermore, similar expression profiles were observed in unstable human plaque. These data suggest that caspase-11 regulates neutrophil recruitment and plaque destabilization in advanced atherosclerotic lesions.
  • Kenta Fujimura, Tadayoshi Karasawa, Takanori Komada, Naoya Yamada, Yoshiko Mizushina, Chintogtokh Baatarjav, Takayoshi Matsumura, Kinya Otsu, Norihiko Takeda, Hiroaki Mizukami, Kazuomi Kario, Masafumi Takahashi
    Journal of molecular and cellular cardiology 180 58-68 2023年7月  
    Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1β and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3-/- mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3-/- mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3-/- mice. LPS-induced SCM was also prevented in Casp1/11-/- mice, but not in Casp11mt, IL-1β-/-, IL-1α-/-, or GSDMD-/- mice. Notably, LPS-induced SCM was apparently prevented in IL-1β-/- mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1β and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.
  • Chintogtokh Baatarjav, Takanori Komada, Tadayoshi Karasawa, Naoya Yamada, Ariunaa Sampilvanjil, Takayoshi Matsumura, Masafumi Takahashi
    Cell death and differentiation 2022年6月23日  
    Rhabdomyolysis is a severe condition that commonly leads to acute kidney injury (AKI). While double-stranded DNA (dsDNA) released from injured muscle can be involved in its pathogenesis, the exact mechanism of how dsDNA contributes to rhabdomyolysis-induced AKI (RIAKI) remains obscure. A dsDNA sensor, absent in melanoma 2 (AIM2), forms an inflammasome and induces gasdermin D (GSDMD) cleavage resulting in inflammatory cell death known as pyroptosis. In this study using a mouse model of RIAKI, we found that Aim2-deficiency led to massive macrophage accumulation resulting in delayed functional recovery and perpetuating fibrosis in the kidney. While Aim2-deficiency compromised RIAKI-induced kidney macrophage pyroptosis, it unexpectedly accelerated aberrant inflammation as demonstrated by CXCR3+CD206+ macrophage accumulation and activation of TBK1-IRF3/NF-κB. Kidney macrophages with intact AIM2 underwent swift pyroptosis without IL-1β release in response to dsDNA. On the other hand, dsDNA-induced Aim2-deficient macrophages escaped from swift pyroptotic elimination and instead engaged STING-TBK1-IRF3/NF-κB signalling, leading to aggravated inflammatory phenotypes. Collectively, these findings shed light on a hitherto unknown immunoregulatory function of macrophage pyroptosis. dsDNA-induced rapid macrophage cell death potentially serves as an anti-inflammatory program and determines the healing process of RIAKI.
  • Tadayoshi Karasawa, Takanori Komada, Naoya Yamada, Emi Aizawa, Yoshiko Mizushina, Sachiko Watanabe, Chintogtokh Baatarjav, Takayoshi Matsumura, Masafumi Takahashi
    eLife 11 2022年5月26日  
    Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome, the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1β. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1β release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.

MISC

 4
  • 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年4月18日  
    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.
  • 秋山 裕輝, 増田 貴博, 岩本 澄也, 杉江 舜, 安部 翔, 松岡 諒, 宮本 友佳, 大舘 孝幸, 中川 早紀, 今井 利美, 駒田 敬則, 鈴木 倫子, 前嶋 明人, 齋藤 修, 長田 太助
    日本透析医学会雑誌 52(Suppl.1) 461-461 2019年5月  
  • 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年  
  • Komada Takanori, Usui Fumitake, Muto Shigeaki, Nagata Daisuke, Kusano Eiji, Takahashi Masafumi
    NEPHROLOGY 19 30-31 2014年5月  

共同研究・競争的資金等の研究課題

 6