IL-10 Dysregulation Underlies Chemokine Insufficiency, Delayed Macrophage Response, and Impaired Healing in Diabetic Wound

Persistent inflammation is a major contributor to healing impairment in diabetic chronic wounds. Paradoxically, diabetic wound environment during the acute phase of healing is completely different in that it exhibits reduced macrophage response due to inadequate expression of CCL2 proinflammatory cytokine. What causes reduction in CCL2 expression in diabetic wound early after injury remains unknown. Here, we report that in contrast to prolonged exposure to high glucose which transforms monocytes proinflammatory, short-term exposure to high glucose causes a rapid monocyte reprograming, manifested by increased expression and secretion of IL-10 which in an autocrine/paracrine fashion, reduces glucose uptake and transforms monocytes into anti-inflammatory phenotype by dampening signaling through toll-like receptors (TLRs). We show that IL-10 expression is significantly increased in diabetic wound during the acute phase of healing, causing significant reductions in TLR signaling and proinflammatory cytokines production, delaying macrophage and leukocyte responses, and underlying healing impairment in diabetic wounds. Importantly, blocking IL-10 signaling during the acute phase of healing improves TLR signaling, increases proinflammatory cytokines production, enhances macrophage and leukocyte responses, and stimulates healing in diabetic wound. We posit that anti-IL-10 strategies have therapeutic potential if added topically after surgical debridement process which resets chronic wounds into acute fresh wounds.