IL-17RA deficiency improves diabetic wound healing and is associated with reduced oxidative stress, inflammation, and NF-κB/JMJD3-related signaling.

Abstract

Diabetic wound healing is delayed by a hostile wound microenvironment characterized by persistent oxidative stress, chronic inflammation, and dysfunction of key reparative cells, including keratinocytes, fibroblasts, endothelial cells, and immune cells. IL-17A/IL-17RA signaling is closely involved in diabetes-associated inflammation, but its role in diabetic wound repair remains incompletely defined. Male C57BL/6NCya-Il17ra knockout and age-matched wild-type (WT) mice were assigned to wild-type non-diabetic (WT-ND), Il17ra knockout non-diabetic (KO-ND), wild-type diabetic (WT-DM), and Il17ra knockout diabetic (KO-DM) groups. Diabetes was induced by streptozotocin, followed by dorsal full-thickness excisional wounding after confirmation of hyperglycemia. STZ-induced diabetic mice exhibited delayed wound closure, lower body weight, and persistently elevated fasting blood glucose. Compared with WT-DM mice, KO-DM mice showed significantly improved wound closure. Il17ra deficiency attenuated diabetes-associated oxidative stress, as indicated by higher SOD, catalase, and GSH levels and lower MDA levels, and reduced systemic and local IL-6, IL-1β, and TNF-α levels. At the molecular level, KO-DM wounds displayed reduced NF-κB p65 phosphorylation and JMJD3 expression, together with partial restoration of H3K27me3. In parallel, Il17ra deficiency suppressed diabetes-induced expression of Cxcl1, Cxcl5, Ccl20, Itga3, and Timp1 while partially restoring Mmp2 and Fgf2 expression. Histologically, KO-DM wounds showed smaller epithelial gaps, thicker granulation tissue, lower inflammatory scores, and greater collagen deposition than WT-DM wounds. Il17ra deficiency promotes diabetic wound healing and is associated with reduced oxidative stress and inflammation, accompanied by attenuation of NF-κB/JMJD3-related molecular and transcriptional abnormalities.