Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor
Gillian S. Ashcroft, Stuart J. Mills, KeJian Lei, Linda Gibbons, Moon-Jin Jeong, Marisu Taniguchi, Matthew Burow, Michael A. Horan, Sharon M. Wahl, Toshinori Nakayama
Gillian S. Ashcroft, Stuart J. Mills, KeJian Lei, Linda Gibbons, Moon-Jin Jeong, Marisu Taniguchi, Matthew Burow, Michael A. Horan, Sharon M. Wahl, Toshinori Nakayama
View: Text | PDF
Article Aging

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Abstract

Characteristic of both chronic wounds and acute wounds that fail to heal are excessive leukocytosis and reduced matrix deposition. Estrogen is a major regulator of wound repair that can reverse age-related impaired wound healing in human and animal models, characterized by a dampened inflammatory response and increased matrix deposited at the wound site. Macrophage migration inhibitory factor (MIF) is a candidate proinflammatory cytokine involved in the hormonal regulation of inflammation. We demonstrate that MIF is upregulated in a distinct spatial and temporal pattern during wound healing and its expression is markedly elevated in wounds of estrogen-deficient mice as compared with intact animals. Wound-healing studies in mice rendered null for the MIF gene have demonstrated that in the absence of MIF, the excessive inflammation and delayed-healing phenotype associated with reduced estrogen is reversed. Moreover, in vitro assays have shown a striking estrogen-mediated decrease in MIF production by activated murine macrophages, a process involving the estrogen receptor. We suggest that estrogen inhibits the local inflammatory response by downregulating MIF, suggesting a specific target for future therapeutic intervention in impaired wound-healing states.

Authors

Gillian S. Ashcroft, Stuart J. Mills, KeJian Lei, Linda Gibbons, Moon-Jin Jeong, Marisu Taniguchi, Matthew Burow, Michael A. Horan, Sharon M. Wahl, Toshinori Nakayama

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
Treatment of MIF null wounds with TGF-β (200 ng per wound) results in de...
Treatment of MIF null wounds with TGF-β (200 ng per wound) results in delayed healing as compared with vehicle-treated wounds (a, top panels). Wounds are representative of day 3 after wounding. Arrows demarcate wound edges. Treatment of MIF null wounds with rhMIF results in impaired healing (a, bottom panels) (day 7 after wounding, 1-μg dose) as compared with vehicle (PBS). Scale bar represents 100 μm. Results represent means ± SEM (n = 5, *P < 0.05). (b) Neutralization of MIF in wild-type OVX mice with anti-MIF antibodies leads to improved healing as compared with vehicle alone (day 3 after wounding). Arrows demarcate wound edges, which cannot be visualized in the OVX mice. Graph illustrates wound areas at day 3 after wounding in a dose-response study with increasing doses of anti-MIF antibodies injected at the time of wounding. Scale bar represents 100 μm. Results represent means ± SEM (n = 5, *P < 0.05, **P < 0.01). C, no injection at wound site; PBS, vehicle control.