No abstract

SummaryDisorders of cutaneous repair can cause disability or death given that skin functions as a protective barrier against the external environment. The inflammatory response triggered by tissue damage is thought to play both positive (e.g., pathogen-killing) and negative (e.g., scarring) roles in repair [1–3]. Inflammatory resolution mediators such as chemerin15 (C15) control the magnitude and duration of the inflammatory response; however, their role in wound repair and scarring is unknown [4–8]. Here, we show that the C15 precursor, chemerin, and its receptor, ChemR23, are both upregulated after skin damage and that the receptor is expressed by macrophages, neutrophils, and keratinocytes. Dynamic live-imaging studies of murine cutaneous wounds demonstrate that C15 delivery dampens the immediate intravascular inflammatory events, including platelet adhesion to neutrophils, an important event in driving leukocyte recruitment. C15 administration indirectly accelerates wound closure while altering fibroblast-mediated collagen deposition and alignment to reduce scarring. Macrophage recruitment is restricted to the immediate wound site rather than spilling extensively into the adjacent tissue as in control wounds, and macrophage phenotype in C15-treated wounds is skewed toward a less inflammatory phenotype with reduced iNOS, increased Arginase-1, and lower wound tumor necrosis factor α (TNF-α) expression. Modulation of inflammatory resolution pathways in acute and chronic wounds may therefore provide a novel therapeutic avenue to improve repair and reduce scarring.

SummaryFor a skin wound to successfully heal, the cut epidermal-edge cells have to migrate forward at the interface between scab and healthy granulation tissue. Much is known about how lead-edge cells migrate, but very little is known about the mechanisms that enable active participation by cells further back. Here we show that ephrin-B1 and its receptor EphB2 are both upregulated in vivo, just for the duration of repair, in the first 70 or so rows of epidermal cells, and this signal leads to downregulation of the molecular components of adherens and tight (but not desmosomal) junctions, leading to loosening between neighbors and enabling shuffle room among epidermal cells. Additionally, this signaling leads to the shutdown of actomyosin stress fibers in these same epidermal cells, which may act to release tension within the wound monolayer. If this signaling axis is perturbed, then disrupted healing is a consequence in mouse and man.