Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor
Open accessAbstract
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.
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Topical application of estrogens or ER agonists in aged females and males can improve healing, partially due to reduced MIF and activation of keratinocytes.
“Topical application of estrogens or ER agonists in both aged females and males can improve healing, which may be partially due to the reduced expression of macrophage migration inhibitory factor (MIF) and activation of keratinocytes [145–147].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [146]
The Introduction reports improved healing with topical estrogen in elderly women and men, and the Discussion proposes ER-mediated reduction of MIF as a mechanism (page numbers unavailable). The paper shows ER agonists inhibiting MIF expression in cells, but does not show that topical ER agonists improve healing in aged people or that keratinocyte activation explains the benefit; it reports MIF localization to keratinocytes instead. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEstrogen is a positive effector in wound healing.
“estrogen has been demonstrated as a positive effector in wound healing.”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [146]
Estrogen is important to wound healing, and its deficiency delays or impairs wound healing.
“Numerous studies have shown that estrogen is important to wound healing, and its deficiency delays or impairs wound healing29–33.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [30]
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- Authors
- Ashcroft, G. S., Mills, S. J., Lei, K., Gibbons, L., Jeong, M.-J., Taniguchi, M., Burow, M., Horan, M. A., Wahl, S. M., & Nakayama, T.
- Affiliations
- University of Manchester (GB)
- National Institutes of Health (US)
- Chiba University (JP)
- Tulane University (US)
- Corresponding author
- Ashcroft, Gillian S.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-05-01
- Volume
- 111
- Issue
- 9
- Pages
- 1309-1318
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC154440
- OpenAlex
- W1981810309
- Cited by
- 335
- References
- 43
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 5 · 2023: 10 · 2022: 12 · 2021: 18 · 2020: 10 · 2019: 18 · 2018: 10 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 24 · 2013: 13 · 2012: 21
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- estrogen, wound healing, macrophage migration inhibitory factor, chronic wounds, estrogen deficiency, estrogen receptor, macrophages, inflammation, estrogen receptor knockout mice, delayed wound healing
- MeSH terms
- Epidermal Cells, Animals, Epidermis, Estrogens, Female, Humans, Lipopolysaccharides, Macrophage Migration-Inhibitory Factors, Macrophages, Male, Mice, Inbred BALB C, Ovariectomy, Receptors, Estrogen, Wound Healing, Down-Regulation, Transforming Growth Factor beta, Mice, Knockout, Mice
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