Epidermal phospholipase Cδ1 regulates granulocyte counts and systemic interleukin-17 levels in mice.
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.
Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo 192-0392, Japan.
Kaori
K
Kanemaru
Yoshikazu
Y
Nakamura
Kojiro
K
Sato
Ryota
R
Kojima
Saori
S
Takahashi
Mami
M
Yamaguchi
Manabu
M
Ichinohe
Hiroshi
H
Kiyonari
Go
G
Shioi
Kenji
K
Kabashima
Kyoko
K
Nakahigashi
Masataka
M
Asagiri
Colin
C
Jamora
Hideki
H
Yamaguchi
Kiyoko
K
Fukami
D016475:3T3 Cells; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000201:enzymology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011565:Psoriasis / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D020381:Interleukin-17; C090140:Whn protein; D010738:Type C Phospholipases