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Sex Dimorphism in Wound Healing: The Roles of Sex Steroids and Macrophage Migration Inhibitory Factor

Faculty of Life Sciences (S.C.G., J.P.D.R., M.J.H., G.S.A.), University of Manchester, Manchester M13 9PT, United Kingdom; and Graduate School of Medicine (T.N.), Chiba University, Chiba 260-8670, Japan

Address all correspondence and requests for reprints to: Gillian S. Ashcroft, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom. E-mail: gillian.s.ashcroft{at}manchester.ac.uk.

That endogenous sex steroid hormones profoundly influence the response to cutaneous injury is well established. How they and other factors combine to direct repair in male and female animals is much less well understood. Using a murine incisional wound-healing model, we investigated the roles of circulating sex steroids, macrophage migration inhibitory factor (MIF) (the mediator of delayed healing in ovariectomized animals), and hormone- and MIF-independent factors in controlling repair. We report that d 3 wounds, of comparable size in intact male and female mice, are significantly larger in ovariectomized female animals than in castrated males, suggesting that native sex hormones mask inherent underlying differences in the ways in which males and females respond to wounding. Wound MIF levels were comparable in intact male and female mice but greater in ovariectomized females than castrated males. Furthermore, wound levels of Jun activation domain-binding protein 1 (JAB1), a key factor by which MIF activates intracellular responses, were increased through ovariectomy and greater in ovariectomized females than castrated males. This difference in wound JAB1 levels may underscore the marked sex difference we observed in the responses of MIF knockout mice to the local application of MIF: healing was impaired in ovariectomized females but not castrated males. Separately, systemic treatment with androgens and estrogens yielded contrasting effects on repair in male and female animals. Collectively, the presented data indicate sex divergence in wound healing to be multifaceted, being strongly influenced by MIF and seemingly limited by the combined actions of gonadal steroids.