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Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.

ABSTRACT: 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.

SUBMITTER: Wu Y

PROVIDER: S-EPMC5109591 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.

Wu Yelin Y Quan Yanchun Y Liu Yuanqi Y Liu Keiwei K Li Hongquan H Jiang Ziwei Z Zhang Tian T Lei Hu H Radek Katherine A KA Li Dongqing D Wang Zhenhua Z Lu Jilong J Wang Wang W Ji Shizhao S Xia Zhaofan Z Lai Yuping Y

Nature communications 20161110

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 ex ...[more]

PMID: 27830702

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Project description:BackgroundType 2 diabetes mellitus (T2DM) and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM.HypothesisLimited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration.MethodsLong Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF) deficiency and resistance in the context of neurodegeneration.ResultsHFD +/- NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT), which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD +/- NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3beta (reflecting increased GSK-3beta activity), glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats.ConclusionsEarly limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of ceramides and probably other toxic lipids in brain.

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Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.

Publications

Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes.

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