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.
Highlights
Dysregulated inflammatory responses are known to impair wound healing in diabetes, but the underlying mechanisms are poorly understood
To confirm that regenerating islet-derived protein 3A (REG3A) is related to impaired wound healing in diabetes, we evaluated a streptozotocin (STZ)-induced experimental type 1 diabetic (T1D) mouse model and found that both mRNA and protein of RegIIIg, a mouse homologue of human REG3A, dramatically decreased in skin wounds of C57BL/6 T1D mice (Fig. 1c–e)
Consistent with decreased inflammation, RegIIIg significantly accelerated wound healing in T1D mice (Fig. 1h,i). These data confirm that RegIIIg is required for the control of inflammatory responses in skin wounds, and that defective REG3A/RegIIIg expression leads to impaired wound healing in diabetes
Summary
Dysregulated inflammatory responses are known to impair wound healing in diabetes, but the underlying mechanisms are poorly understood. Compared with wounds from normal patients, the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-a and interleukin (IL)-6, is dramatically increased to induce prolonged leukocyte infiltration in diabetic wound tissues[4,9,10], while the neutralization of TNF-a inhibits keratinocyte apoptosis to improve wound closure in diabetic wounds[11,12,13,14]. These observations suggest that the dynamic regulation of pro-inflammatory cytokine production might be an effective strategy for the management of wound repair in diabetes. Whether REG3A enables to control TLR-mediated inflammatory responses in diabetic skin wounds remains completely unknown
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