Kaori Kanemaru, Yoshikazu Nakamura, Kojiro Sato, Ryota Kojima, Saori Takahashi, Mami Yamaguchi, Manabu Ichinohe, Hiroshi Kiyonari, Go Shioi, Kenji Kabashima, Kyoko Nakahigashi, Masataka Asagiri, Colin Jamora, Hideki Yamaguchi, Kiyoko Fukami
NATURE COMMUNICATIONS 3(963) 2012年7月 査読有り
Phospholipase C is a key enzyme in phosphoinositide turnover. Although its functions have been extensively studied at the cellular level, many questions remain concerning its functions at the organ and individual animal levels. Here we demonstrate that mice lacking phospholipase C delta 1 develop granulocytosis associated with elevated serum levels of the granulopoietic cytokine interleukin-17. Re-introduction of phospholipase C delta 1 into keratinocytes of phospholipase C delta 1-deficient mice reverses this phenotype, whereas conditional ablation of phospholipase C delta 1 in keratinocytes recreates it. Interleukin-17 and its key upstream regulator interleukin-23 are also upregulated in epidermis. Loss of phospholipase C delta 1 from keratinocytes causes features of interleukin-17-associated inflammatory skin diseases. Phospholipase C delta 1 protein is downregulated in the epidermis of human psoriatic skin and in a mouse model of psoriasis. These results demonstrate that phosphoinositide turnover in keratinocytes regulates not only local inflammatory responses but also serum cytokine levels and systemic leukocyte counts, and affects distant haematopoietic organs.
