IL-10 Dysregulation Underlies Chemokine Insufficiency, Delayed Macrophage Response, and Impaired Healing in Diabetic Wounds.
IL-10 Dysregulation Underlies Chemokine Insufficiency, Delayed Macrophage Response, and Impaired Healing in Diabetic Wounds.
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DOI：
10.1016/j.jid.2021.08.428
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Shafikhani SH
中科院分区：
文献类型：
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作者：
Roy R;Zayas J;Mohamed MF;Aboonabi A;Delgado K;Wallace J;Bayat M;Kuzel TM;Reiser J;Shafikhani SH
持续性炎症是糖尿病慢性创面愈合障碍的主要原因。矛盾的是，糖尿病愈合急性期的创面环境完全不同，因为CCL2促炎细胞因子表达不足，导致巨噬细胞反应减弱。糖尿病创面伤后早期CCL2表达降低的原因尚不清楚。在此，我们报道，与长期暴露于高糖可转化单核细胞炎症反应相反，短期暴露于高糖可导致单核细胞快速重编程，表现为IL-10的表达和分泌增加，IL-10以自分泌/旁分泌的方式减少葡萄糖摄取，并通过抑制Toll样受体(Toll-like Receptor，TLRs)的信号而将单核细胞转化为抗炎表型。我们发现，在糖尿病创面愈合的急性期，IL-10的表达显著增加，导致TLR信号和促炎细胞因子的产生显著减少，延迟巨噬细胞和白细胞的反应，并导致糖尿病创面潜在的愈合障碍。重要的是，在愈合的急性期阻断IL-10信号可以改善TLR信号，增加促炎细胞因子的产生，增强巨噬细胞和白细胞的反应，并促进糖尿病伤口的愈合。我们假设，如果在外科清创过程中将慢性创面重置为急性新鲜创面后局部添加抗IL-10策略，则具有治疗潜力。
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.