Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor
Gillian S. Ashcroft, … , Sharon M. Wahl, Toshinori Nakayama
Gillian S. Ashcroft, … , Sharon M. Wahl, Toshinori Nakayama
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1309-1318. https://doi.org/10.1172/JCI16288.
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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

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Figure 4

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Reduced inflammation in the MIF null wounds. (a) An absence of MIF leads...
Reduced inflammation in the MIF null wounds. (a) An absence of MIF leads to reduced wound blood-vessel area (vessel area presented as a percentage of total wound area) at day 7; however, an absence of estrogen has no effect on neovascularization. Results represent means ± SEM (n = 4, *P < 0.05 for comparisons between intact null and intact wild-type or OVX null and OVX wild-type). (b) Mac3 staining illustrates increased inflammatory cell infiltrate in the OVX wild-type wounds as compared with the OVX MIF null wounds at day 3. Scale bars represent 20 μm. Cell numbers per unit area were quantified at day 3 (c). Results represent means ± SEM (n = 7–10 for each group, *P < 0.05). (d) TNF-α protein levels were increased in the wild-type OVX wounds as compared with the MIF null OVX wounds from days 3–14 after wounding (d, graph) by quantification of immunostaining. Normal skin is scored as 0. Results represent medians (black lines across boxes), boxes represent interquartile ranges, and the bars extending from the boxes indicate the highest and lowest values (n = 7, *P < 0.05). All data are taken from OVX mice. Left panels represent day-3 immunostaining, illustrating increased cell numbers positive for TNF-α in the wild-type OVX wounds. Scale bars represent 50 μm.