Resolution Mediator Chemerin15 Reprograms the Wound Microenvironment to Promote Repair and Reduce Scarring

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.

Myofibroblasts

“…Conditional depletion of macrophages has been shown to reduce liver fibrosis when induced early, but had pro-fibrotic effects when induced at advanced stages of fibrosis (Duffield et al, 2005). Macrophages are now understood to exist in a spectrum of different activation (polarization) types that control different phases of healing and it will be important to target specific macrophages to achieve scarless healing (Cash et al, 2014;Davies et al, 2013;Friedman et al, 2013;Lucas et al, 2010;Mantovani et al, 2013;Martinez and Gordon, 2014;Mosser and Edwards, 2008;Wynn et al, 2013).…”

Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone

“…Chemerin-15, a synthetic peptide, signals via Cmklr1 to elicit many of the same biological effects as chemerin (Cash et al 2008). Cash et al (2014) reported that chemerin-15 alters collagen deposition in injured skin. Since chemerin-15 and chemerin signal via Cmklr1 (Cash et al 2008;Bondue et al 2011), it is plausible that chemerin-Cmklr1 signaling modifies collagen deposition in skin as well as in other organs, including the lungs, a phenomenon that would significantly impact the quasistatic elastic properties of the respiratory system.…”

Myeloid Cells in Cutaneous Wound Repair

“…These pathways offer enormous potential to therapeutically modulate the resolution phase of inflammation and thus impact on the repair process (158,160). Indeed, we have previously shown that topical application of the peptide resolution mediator chemerin15 dampens the wound inflammatory response and skews the Mϕ phenotype to one typically associated with repair (reduced inducible NOS and TNF-α; increased arginase-1), resulting in accelerated healing with reduced scarring (161).…”