title: 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. 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. 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.
authors.affiliation: School of Physiology & Pharmacology, Medical Sciences, University Walk, Bristol University, Bristol BS8 1TD, UK; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK; Calvin, Phoebe, and Joan Snyder Institute for Infection, Immunity, & Inflammation, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: jenna.cash@bristol.ac.uk.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Cash
authors.affiliation: School of Biochemistry, Medical Sciences, University Walk, Bristol University, Bristol BS8 1TD, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bass
authors.affiliation: School of Biochemistry, Medical Sciences, University Walk, Bristol University, Bristol BS8 1TD, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PZ, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Barnes
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Infection, Immunity, & Inflammation, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.affiliation: School of Physiology & Pharmacology, Medical Sciences, University Walk, Bristol University, Bristol BS8 1TD, UK; School of Biochemistry, Medical Sciences, University Walk, Bristol University, Bristol BS8 1TD, UK. Electronic address: paul.martin@bristol.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D002630:Chemotactic Factors / Q000235:genetics* / Q000378:metabolism; D002921:Cicatrix; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012867:Skin; D014945:Wound Healing
chemical_list: D018925:Chemokines; D002630:Chemotactic Factors; C000591279:GPR1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; C523686:chemerin protein, mouse; C000589458:chemerin15 peptide, mouse