Correction of MFG-E8 Resolves Inflammation and Promotes Cutaneous Wound Healing in Diabetes

Abstract

Milk fat globule EGF factor 8 (MFG-E8) is a peripheral glycoprotein which acts as a bridging molecule between the macrophage and apoptotic cells thus executing a pivotal role in the scavenging of apoptotic cells from affected tissue. We have previously reported that apoptotic cell clearance activity or efferocytosis is compromised in diabetic wound macrophages. In this work we test the hypothesis that MFG-E8 helps resolve inflammation, supports angiogenesis and accelerates wound closure. MFG-E8−/− mice, displayed impaired efferocytosis associated with exaggerated inflammatory response, poor angiogenesis and wound closure. Wound macrophage-derived MFG-E8 was recognized as a critical driver of wound angiogenesis. Transplantation of MFG-E8−/− bone marrow to MFG-E8+/+ mice resulted in impaired wound closure and compromised wound vascularization. On the other hand, MFG-E8−/− mice that received wild-type bone marrow showed improved wound closure and improved wound vascularization. Hyperglycemia and exposure to advanced glycated end products inactivated MFG-E8 recognizing a key mechanism that complicates diabetic wound healing. Diabetic db/db mice suffered from impaired efferocytosis accompanied with persistent inflammation and slow wound closure. Topical rMFG-E8 induced resolution of wound inflammation, improvements in angiogenesis and acceleration of closure upholding the potential of MFG-E8 directed therapeutics in diabetic wound care.

Milk fat globule epidermal growth factor 8 inhibits periodontitis in non‐human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans

“…, Das et al. ), MFG‐E8 may play an important role in the homeostasis of the periodontium and other barrier sites, which are constantly challenged by microbial or inflammatory stimuli. A unique feature of the periodontium compared with other mucosal sites (e.g.…”

Stabilized collagen matrix dressing improves wound macrophage function and epithelialization

“…Wound imaging was performed at d 0 and 14 by using a digital camera (Canon Power Shot S6; Melville, NY, USA), and the wound area was calculated by ImageJ software (Image Processing and Analysis in Java; National Institutes of Health, Bethesda, MD, USA; https://imagej.nih.gov/ij/) (27).…”

“…Two PC sponges were implanted subcutaneously on the back of 8 wk old C57BL/6 mice, with 2 sPCM on the opposite side of the midline. Macrophages were isolated from the sponges via compression in sterile PBS and CD11b magnetic sorting as previously described (27,28).…”

“…Apoptotic cell clearance assay was conducted using wound macrophages cocultured with thymocytes ex vivo, as previously described (27,28). In brief, CD11b-selected wound macrophages were cocultured for 1 h at 37°C in 8-well chambered slides with apoptotic (5 mM dexamethasone treated) thymocytes previously labeled with pHrodo Red succinimidyl ester (P36600; Thermo Fisher Scientific, Waltham, MA, USA) for 12 h. Cells were washed in medium to remove excess nonengulfed cells.…”

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“…MFG-E8 binds to apoptotic cells, enhances the phagocytosis of apoptotic cells by macrophages and provides an anti-inflammatory function [8,9]. Topical recombinant MFG-E8 treatment induces resolution of wound inflammation, and improvement in angiogenesis [10]. Suppressor of cytokine signaling-3 (SOCS-3) plays an important role in negative regulation of inflammatory response [11].…”