Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice
By S. Khanna, S. Biswas, Y. Shang, E. Collard, A. Azad, Courtney Y. Kauh, V. Bhasker, G. Gordillo, Chandan K. Sen, Sashwati Roy. PLoS ONE, 2010
632 citations recorded by the source corpus.
Background 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. Methodology/Principal Findings Macrophages 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/Significance Taken 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.
Subfields: Immunology, Rehabilitation
View Paper: https://www.semanticscholar.org/paper/53f48accc7eddbb01b58b2e1b2b0515e1cc04113
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In Immunology
- Paulina Krzyszczyk
- L. Cañedo-Dorantes
- Mara Cañedo-Ayala
- Andre F. Palmer
- G. Gurtner
- Francois Berthiaume
- L. DiPietro
- Melanie Rodrigues
In Rehabilitation
Citations in the corpus
- Diabetes and Wound Angiogenesis (2017, background): “showed that macrophages at the wound site of db/db mice showed decreased efferocytosis, leading to increased apoptotic burden and inflammatory profile in the wound [83].”
- Wound Healing: A Cellular Perspective. (2019, background): “A lag in macrophage activation causes impaired efferocytosis (216) and a persistence of wound debris, apoptotic cells, and neutrophils.”
- Transition from inflammation to proliferation: a critical step during wound healing (2016, background): “Impairment of efferocytosis of macrophages, observed in diabetic wounds, prolongs the inflammatory phase and delays healing [70].”
- Skin Acute Wound Healing: A Comprehensive Review (2019, background): “Thus, diabetic foot ulcers exhibit a chronic inflammatory status and altered molecular environment including growth factors, cytokines, and proteases [173] and inflammatory cells present a dysfunctional phenotype [174, 175].”
- The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes (2018, background): “Diabetic patients have macrophages with reduced apoptotic clearance activity because of the effects of hyperglycemia and advanced glycation endproducts (Khanna et al., 2010; Hesketh et al., 2017).”
- Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing (2017, background): “Increased apoptosis in an acute wound model leads to an increased inflammatory response with reduced anti-inflammatory cytokines [48].”