The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury.
Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, P.R. China. yplai@bio.ecnu.edu.cn
Yuping
Y
Lai
Dongqing
D
Li
Changwei
C
Li
Beda
B
Muehleisen
Katherine A
KA
Radek
Hyun Jeong
HJ
Park
Ziwei
Z
Jiang
Zhiheng
Z
Li
Hu
H
Lei
Yanchun
Y
Quan
Tian
T
Zhang
Yelin
Y
Wu
Paul
P
Kotol
Shin
S
Morizane
Tissa R
TR
Hata
Keiji
K
Iwatsuki
Ce
C
Tang
Richard L
RL
Gallo
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D004817:Epidermis / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C110774:EXTL3 protein, human; D020381:Interleukin-17; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; C494437:REG3G protein, human; C000612143:Reg3a protein, mouse; D017351:N-Acetylglucosaminyltransferases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt