Local Arginase 1 Activity Is Required for Cutaneous Wound Healing

被引:171
作者
Campbell, Laura [1 ]
Saville, Charis R. [1 ]
Murray, Peter J. [2 ,3 ]
Cruickshank, Sheena M. [4 ]
Hardman, Matthew J. [1 ]
机构
[1] Univ Manchester, Healing Fdn Ctr, Fac Life Sci, Manchester M13 9PT, Lancs, England
[2] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA
[3] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA
[4] Univ Manchester, Manchester Immunol Grp, Fac Life Sci, Manchester M13 9PT, Lancs, England
关键词
NITRIC-OXIDE SYNTHASE; MIGRATION INHIBITORY FACTOR; OVARIECTOMIZED FEMALE MICE; ARGININE METABOLISM; PRESSURE ULCERS; KNOCKOUT MICE; AMINO-ACID; IN-VIVO; EXPRESSION; MACROPHAGES;
D O I
10.1038/jid.2013.164
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
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.
引用
收藏
页码:2461 / 2470
页数:10
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