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

Abstract

Disorders 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 [1Martin P. D’Souza D. Martin J. Grose R. Cooper L. Maki R. McKercher S.R. Wound healing in the PU.1 null mouse—tissue repair is not dependent on inflammatory cells.Curr. Biol. 2003; 13: 1122-1128Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, 2Stramer B.M. Mori R. Martin P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair.J. Invest. Dermatol. 2007; 127: 1009-1017Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 3Silva M.T. When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system.J. Leukoc. Biol. 2010; 87: 93-106Crossref PubMed Scopus (215) Google Scholar]. 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 [4Gilroy D.W. Lawrence T. Perretti M. Rossi A.G. Inflammatory resolution: new opportunities for drug discovery.Nat. Rev. Drug Discov. 2004; 3: 401-416Crossref PubMed Scopus (642) Google Scholar, 5Serhan C.N. Brain S.D. Buckley C.D. Gilroy D.W. Haslett C. O’Neill L.A. Perretti M. Rossi A.G. Wallace J.L. Resolution of inflammation: state of the art, definitions and terms.FASEB J. 2007; 21: 325-332Crossref PubMed Scopus (847) Google Scholar, 6Cash J.L. Bena S. Headland S.E. McArthur S. Brancaleone V. Perretti M. Chemerin15 inhibits neutrophil-mediated vascular inflammation and myocardial ischemia-reperfusion injury through ChemR23.EMBO Rep. 2013; 14: 999-1007Crossref PubMed Scopus (40) Google Scholar, 7Cash J.L. Christian A.R. Greaves D.R. Chemerin peptides promote phagocytosis in a ChemR23- and Syk-dependent manner.J. Immunol. 2010; 184: 5315-5324Crossref PubMed Scopus (55) Google Scholar, 8Cash J.L. Hart R. Russ A. Dixon J.P. Colledge W.H. Doran J. Hendrick A.G. Carlton M.B. Greaves D.R. Synthetic chemerin-derived peptides suppress inflammation through ChemR23.J. Exp. Med. 2008; 205: 767-775Crossref PubMed Scopus (303) Google Scholar]. 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.