Estrogen Induces the Alternative Activation of Macrophages through Binding to Estrogen Receptor-alpha

Belboul, Amina, Ashworth, Jason ORCID: https://orcid.org/0000-0001-7045-7899, Fadel, Abdulmannan, Mcloughlin, Jessica, Mahmoud, Ayman M ORCID: https://orcid.org/0000-0003-0279-6500 and El Mohtadi, Mohamed (2025) Estrogen Induces the Alternative Activation of Macrophages through Binding to Estrogen Receptor-alpha. Experimental and Molecular Pathology, 143. 104971. ISSN 0014-4800 (In Press)

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Abstract

Age-related impaired wounds represent a major health burden resulting in considerable morbidity and mortality in the elderly. When injury occurs, monocytes migrate to the damaged site and undergo differentiation into tissue-resident macrophages, which are crucial for wound repair. For proper resolution of the inflammatory response, macrophages differentiate into two distinct phenotypes classified as classically-activated pro-inflammatory and alternatively-activated anti-inflammatory macrophages. Pro-inflammatory macrophages are commonly linked with pro-inflammatory events, while anti-inflammatory macrophages are known to be pro-regenerative. The age-related delay in wound repair is often attributed to the age-related decrease in local and systemic estrogen levels in both genders. However, despite its well-documented anti-inflammatory effect in wound healing, the role of estrogen and involvement of Estrogen Receptors (ERs) in macrophage polarization has gained little attention to date. To investigate the impact of estrogen and ERs on the polarization of macrophages, monocyte-derived macrophages were pre-treated with estrogen, ER-alpha agonist/antagonist or ER-beta agonist/antagonist prior to stimulation with LPS/IFN-γ or IL-4/IL-13 to produce pro-inflammatory or anti-inflammatory macrophages. Our findings confirm that estrogen promotes the alternative activation of macrophages via possible ER-α signalling. Selective targeting of ER-α with agents like PPT could potentially lead to the development of novel therapies to treat excessive inflammation in impaired wounds.