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

Ruchi Roy, Janet Zayas, Mohamed F Mohamed, Anahita Aboonabi, Kaylee Delgado, Jennillee Wallace, Mohammad Bayat, Timothy M Kuzel, Jochen Reiser, Sasha H Shafikhani

The Journal of investigative dermatology 2022 Mar

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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 because it exhibits a reduced macrophage response owing to inadequate expression of CCL2 proinflammatory cytokine. What causes a reduction in CCL2 expression in diabetic wounds early after injury remains unknown. In this study, we report that in contrast to prolonged exposure to high glucose, which makes monocytes proinflammatory, short-term exposure to high glucose causes a rapid monocyte reprogramming, manifested by increased expression and secretion of IL-10, which in an autocrine/paracrine fashion reduces glucose uptake and transforms monocytes into an anti-inflammatory phenotype by dampening signaling through toll-like receptors. We show that IL-10 expression is significantly increased in diabetic wounds during the acute phase of healing, causing significant reductions in toll-like receptor signaling and proinflammatory cytokine 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 toll-like receptor signaling, increases proinflammatory cytokine production, enhances macrophage and leukocyte responses, and stimulates healing in diabetic wounds. We posit that anti-IL-10 strategies have therapeutic potential if added topically after surgical debridement, which resets chronic wounds into acute fresh wounds. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Ruchi Roy, Janet Zayas, Mohamed F Mohamed, Anahita Aboonabi, Kaylee Delgado, Jennillee Wallace, Mohammad Bayat, Timothy M Kuzel, Jochen Reiser, Sasha H Shafikhani. IL-10 Dysregulation Underlies Chemokine Insufficiency, Delayed Macrophage Response, and Impaired Healing in Diabetic Wounds. The Journal of investigative dermatology. 2022 Mar;142(3 Pt A):692-704.e14