title: Local arginase 1 activity is required for cutaneous wound healing.
abstract: Chronic nonhealing wounds in the elderly population are associated with a prolonged and excessive inflammatory response, which is widely hypothesized to impede healing. Previous studies have linked alterations in local L-arginine metabolism, principally mediated by the enzymes arginase (Arg) and inducible nitric oxide synthase (iNOS), to pathological wound healing. Over subsequent years, interest in Arg/iNOS has focused on the classical versus alternatively activated (M1/M2) macrophage paradigm. Although the role of iNOS during healing has been studied, Arg contribution to healing remains unclear. Here, we report that Arg is dynamically regulated during acute wound healing. Pharmacological inhibition of local Arg activity directly perturbed healing, as did Tie2-cre-mediated deletion of Arg1, revealing the importance of Arg1 during healing. Inhibition or depletion of Arg did not alter alternatively activated macrophage numbers but instead was associated with increased inflammation, including increased influx of iNOS(+) cells and defects in matrix deposition. Finally, we reveal that in preclinical murine models reduced Arg expression directly correlates with delayed healing, and as such may represent an important future therapeutic target.
authors.affiliation: The Healing Foundation Centre, Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Campbell
authors.affiliation: The Healing Foundation Centre, Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Charis R
authors.initials: CR
authors.lastname: Saville
authors.affiliation: Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.affiliation: Manchester Immunology Group, Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Sheena M
authors.initials: SM
authors.lastname: Cruickshank
authors.affiliation: The Healing Foundation Centre, Faculty of Life Sciences, The University of Manchester, Manchester, UK. Electronic address: matthew.j.hardman@manchester.ac.uk.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hardman
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D003872:Dermatitis / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism; D005260:Female; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics; D012867:Skin / Q000201:enzymology* / Q000276:immunology / Q000293:injuries*; D014945:Wound Healing / Q000276:immunology / Q000502:physiology*
chemical_list: D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase
references.citation: J Clin Invest. 1994 Nov;94(5):2036-44
references.pmid: 7525653
references.citation: J Immunol Methods. 1994 Sep 14;174(1-2):231-5
references.pmid: 8083527
references.citation: J Cell Sci. 2009 Sep 15;122(Pt 18):3209-13
references.pmid: 19726630
references.citation: J Leukoc Biol. 2010 Jul;88(1):159-68
references.pmid: 20360403
references.citation: Nitric Oxide. 2009 Nov-Dec;21(3-4):175-83
references.pmid: 19638312
references.citation: J Clin Invest. 1998 Mar 1;101(5):967-71
references.pmid: 9486966
references.citation: Respir Res. 2006 Jan 12;7:6
references.pmid: 16409620
references.citation: Immunity. 2010 May 28;32(5):593-604
references.pmid: 20510870
references.citation: J Surg Res. 2002 Jun 1;105(1):35-42
references.pmid: 12069499
references.citation: Biol Res Nurs. 2008 Oct;10(2):87-92
references.pmid: 18829591
references.citation: Trends Cell Biol. 2005 Nov;15(11):599-607
references.pmid: 16202600
references.citation: Wound Repair Regen. 2003 Nov-Dec;11(6):490-5
references.pmid: 14617291
references.citation: J Immunol. 2001 Dec 1;167(11):6533-44
references.pmid: 11714822
references.citation: Endocrinology. 2008 Feb;149(2):551-7
references.pmid: 17974625
references.citation: J Pharmacol Exp Ther. 1999 Sep;290(3):1409-16
references.pmid: 10454520
references.citation: Wound Repair Regen. 2012 Mar-Apr;20(2):203-13
references.pmid: 22380690
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Jul;299(1):L17-24
references.pmid: 20382750
references.citation: J Immunol. 1990 May 15;144(10):3877-80
references.pmid: 2332635
references.citation: Br J Dermatol. 2010 Jul;163(1):193-6
references.pmid: 20331451
references.citation: Blood. 2007 Apr 1;109(7):3084-7
references.pmid: 17119118
references.citation: Ann Surg. 2002 Sep;236(3):369-74; discussion 374-5
references.pmid: 12192323
references.citation: J Clin Invest. 2011 Mar;121(3):985-97
references.pmid: 21317534
references.citation: Genome Biol. 2008;9(5):R80
references.pmid: 18477406
references.citation: Immunobiology. 2007;212(9-10):795-812
references.pmid: 18086380
references.citation: J Immunol. 2010 Sep 1;185(5):3076-85
references.pmid: 20668217
references.citation: In Vivo. 2009 Jul-Aug;23(4):515-8
references.pmid: 19567384
references.citation: N Engl J Med. 1999 Sep 2;341(10):738-46
references.pmid: 10471461
references.citation: J Clin Invest. 2003 May;111(9):1309-18
references.pmid: 12727922
references.citation: Surgery. 2000 Aug;128(2):374-8
references.pmid: 10923019
references.citation: Nitric Oxide. 1999 Dec;3(6):427-38
references.pmid: 10637120
references.citation: Surgery. 2002 Nov;132(5):866-76
references.pmid: 12464872
references.citation: Mol Cell Endocrinol. 2010 Jun 10;321(2):184-93
references.pmid: 20193736
references.citation: J Invest Dermatol. 1998 Nov;111(5):850-7
references.pmid: 9804349
references.citation: Surgery. 1990 Aug;108(2):331-6; discussion 336-7
references.pmid: 2382229
references.citation: J Pathol. 2000 Aug;191(4):434-42
references.pmid: 10918219
references.citation: Surgery. 1978 Aug;84(2):224-30
references.pmid: 684614
references.citation: Br J Pharmacol. 2009 Jul;157(6):922-30
references.pmid: 19508396
references.citation: J Leukoc Biol. 2010 Jan;87(1):59-67
references.pmid: 20052800
references.citation: PLoS Pathog. 2009 Apr;5(4):e1000371
references.pmid: 19360123
references.citation: Diabetologia. 2002 Jul;45(7):1011-6
references.pmid: 12136400
references.citation: Curr Protoc Immunol. 2008 Nov;Chapter 14:Unit 14.2
references.pmid: 19016446
references.citation: Am J Pathol. 2005 Dec;167(6):1561-74
references.pmid: 16314470
references.citation: Nat Immunol. 2008 Dec;9(12):1399-406
references.pmid: 18978793
references.citation: J Clin Invest. 2002 Sep;110(5):615-24
references.pmid: 12208862
references.citation: Comp Biochem Physiol B Biochem Mol Biol. 1996 May;114(1):107-32
references.pmid: 8759304
references.citation: Int J Pediatr Otorhinolaryngol. 2005 Mar;69(3):381-5
references.pmid: 15733598
references.citation: J Invest Dermatol. 2003 Dec;121(6):1544-51
references.pmid: 14675208
references.citation: Diabetologia. 1999 Jun;42(6):748-57
references.pmid: 10382596
references.citation: Surgery. 2012 Feb;151(2):287-95
references.pmid: 21975291
references.citation: J Transl Med. 2007 Feb 21;5:11
references.pmid: 17313672