Epidermal phospholipase Cδ1 regulates granulocyte counts and systemic interleukin-17 levels in mice

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 and Kiyoko Fukami ()
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Kaori Kanemaru: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences
Yoshikazu Nakamura: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences
Kojiro Sato: Faculty of Medicine, Saitama Medical University
Ryota Kojima: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences
Saori Takahashi: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences
Mami Yamaguchi: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences
Manabu Ichinohe: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences
Hiroshi Kiyonari: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology
Go Shioi: Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology
Kenji Kabashima: Graduate School of Medicine, Kyoto University
Kyoko Nakahigashi: Graduate School of Medicine, Kyoto University
Masataka Asagiri: University of California San Diego
Colin Jamora: Section of Cell and Developmental Biology, University of California San Diego
Hideki Yamaguchi: National Cancer Center Research Institute
Kiyoko Fukami: Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract 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 Cδ1 develop granulocytosis associated with elevated serum levels of the granulopoietic cytokine interleukin-17. Re-introduction of phospholipase Cδ1 into keratinocytes of phospholipase Cδ1-deficient mice reverses this phenotype, whereas conditional ablation of phospholipase Cδ1 in keratinocytes recreates it. Interleukin-17 and its key upstream regulator interleukin-23 are also upregulated in epidermis. Loss of phospholipase Cδ1 from keratinocytes causes features of interleukin-17-associated inflammatory skin diseases. Phospholipase Cδ1 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.

Date: 2012
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DOI: 10.1038/ncomms1960

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