Heterogeneity and high versatility are the characteristic features of the cells of monocyte-macrophage lineage. The mononuclear phagocyte system, derived from the bone marrow progenitor cells, is primarily composed of monocytes, macrophages, and dendritic cells. In regenerative tissues, a central role of monocyte-derived macrophages and paracrine factors secreted by these cells is indisputable. Macrophages are highly plastic cells. On the basis of environmental cues and molecular mediators, these cells differentiate to proinflammatory type I macrophage (M1) or anti-inflammatory or proreparative type II macrophage (M2) phenotypes and transdifferentiate into other cell types. Given a central role in tissue repair and regeneration, the review focuses on the heterogeneity of monocytes and macrophages with current known mechanisms of differentiation and plasticity, including microenvironmental cues and molecular mediators, such as noncoding RNAs. (Am J Pathol 2015, 185: 2596e2606; http://dx

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.

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Collagenases are useful in enzymatic wound debridement. Clostridial collagenase, marketed as Collagenase Santyl Ointment (CSO), is FDA approved for such use. Building on the scientific premise that collagenases as well as collagen degradation products may regulate immune cell function, we sought to investigate the potential role of CSO in wound inflammation. We tested the hypothesis that in addition to enacting debridement, CSO contributes to the resolution of persistent wound inflammation. Wound macrophages were isolated from PVA sponges loaded with CSO or petrolatum and implanted in mice. Significant increase in pro-reparative and decrease in pro-inflammatory polarization was noted in macrophages of acute as well as diabetic wounds. Wound macrophages from CSO-treated group displayed increased production of anti-inflammatory cytokines IL-10 and TGF-β, and decreased levels of pro-inflammatory cytokines TNF-α and IL-1β. The active ingredient of CSO, CS-API, induced the expression of mϕheal /M(IL-4) polarization markers ex vivo. CS-API treatment attenuated transactivation of NF-κB and significantly induced STAT6 phosphorylation. A significant role of a novel PGE2-EP4 pathway in CS-API induced STAT6 activation and the mϕheal /M(IL-4) polarization was identified. Taken together, findings of this work reposition CSO as a potential agent that may be effective in resolving wound inflammation, including diabetic wounds.

Decellularized matrices of biologic tissue have performed well as wound care dressings. Extracellular matrix‐based dressings are subject to rapid degradation by excessive protease activity at the wound environment. Stabilized, acellular, equine pericardial collagen matrix (sPCM) wound care dressing is flexible cross‐linked proteolytic enzyme degradation resistant. sPCM was structurally characterized utilizing scanning electron and atomic force microscopy. In murine excisional wounds, sPCM was effective in mounting an acute inflammatory response. Postwound inflammation resolved rapidly, as indicated by elevated levels of IL‐10, arginase‐1, and VEGF, and lowering of IL‐lβ and TNF‐α. sPCM induced antimicrobial proteins S100A9 and β‐defensin‐1 in keratinocytes. Adherence of Pseudomonas aeruginosa and Staphylococcus aureus on sPCM pre‐exposed to host immune cells in vivo was inhibited. Excisional wounds dressed with sPCM showed complete closure at d 14, while control wounds remained open. sPCM accelerated wound re‐epithelialization. sPCM not only accelerated wound closure but also improved the quality of healing by increased collagen deposition and maturation. Thus, sPCM is capable of presenting scaffold functionality during the course of wound healing. In addition to inducing endogenous antimicrobial defense systems, the dressing itself has properties that minimize biofilm formation. It mounts robust inflammation, a process that rapidly resolves, making way for wound healing to advance.—El Masry, M. S., Chaffee, S., Das Ghatak, P., Mathew‐Steiner, S. S., Das, A., Higuita‐Castro, N., Roy, S., Anani, R. A., Sen, C. K. Stabilized collagen matrix dressing improves wound macrophage function and epithelialization. FASEB J. 33, 2144–2155 (2019). http://www.fasebj.org