Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.
Dysregulated inflammatory responses are known to impair wound healing in diabetes, but the underlying mechanisms are poorly understood. Here we show that the antimicrobial protein REG3A controls TLR3-mediated inflammation after skin injury. This control is mediated by REG3A-induced SHP-1 protein, and acts selectively on TLR3-activated JNK2. In diabetic mouse skin, hyperglycaemia inhibits the expression of IL-17-induced IL-33 via glucose glycation. The decrease in cutaneous IL-33 reduces REG3A expression in epidermal keratinocytes. The reduction in REG3A is associated with lower levels of SHP-1, which normally inhibits TLR3-induced JNK2 phosphorylation, thereby increasing inflammation in skin wounds. To our knowledge, these findings show for the first time that REG3A can modulate specific cutaneous inflammatory responses and that the decrease in cutaneous REG3A exacerbates inflammation in diabetic skin wounds.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Yelin
Y
Wu
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Yanchun
Y
Quan
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Yuanqi
Y
Liu
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Keiwei
K
Liu
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Hongquan
H
Li
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Ziwei
Z
Jiang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Tian
T
Zhang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Hu
H
Lei
Department of Surgery, Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois 60153, USA.
Katherine A
KA
Radek
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Dongqing
D
Li
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Zhenhua
Z
Wang
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Jilong
J
Lu
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Wang
W
Wang
Burn Institute of Chinese PLA and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Shizhao
S
Ji
Burn Institute of Chinese PLA and Department of Burn Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Zhaofan
Z
Xia
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Yuping
Y
Lai
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D000073718:Pancreatitis-Associated Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D051196:Toll-Like Receptor 3