Abstract
BackgroundChronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing.Methodology/Principal FindingsMacrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode.Conclusions/SignificanceTaken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.
Highlights
The Centers for Disease Control and Prevention (CDC) report that diabetes affects nearly 21 million Americans i.e.,7% of the U.S population
Findings of this study collectively present maiden evidence supporting that increased count of apoptotic cells in cutaneous wounds of diabetic mice and humans is associated with compromised dead cell clearance activity of wound macrophages
The major conclusions of this study are that: i) diabetic wounds have increased apoptotic cells load which is in part due to impaired apoptotic clearance activity of the macrophages at the diabetic wound site
Summary
The Centers for Disease Control and Prevention (CDC) report that diabetes affects nearly 21 million Americans i.e., ,7% of the U.S population. Impairment of cutaneous wound healing is a debilitating complication commonly encountered during diabetes mellitus. Foot ulcers represent the most prevalent diabetic wounds and frequently lead to limb amputations. Diabetic ulcers are characterized by a chronic inflammatory state primarily manifested by imbalances in pro- and antiinflammatory cytokines [3]. Transient self-resolving inflammation is essential for successful wound healing. Diabetic macrophages produce high levels of proinflammatory cytokines [8,9].The causative factors underlying the chronic inflammatory state of diabetic wounds remain to be characterized. Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing
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