Belboul Amina, Ashworth Jason, Fadel Abdulmannan, Mcloughlin Jessica, Mahmoud Ayman, El Mohtadi Mohamed
Department of Life Sciences, Manchester Metropolitan University, Chester Street, Manchester, M1 5GD, UK.
Department of Nutrition and Health, United Arab Emirates University, Al Ain, P.O BOX 15551, United Arab Emirates.
Exp Mol Pathol. 2025 May 20;143:104971. doi: 10.1016/j.yexmp.2025.104971.
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-activatedpro-inflammatory and alternatively-activatedanti-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.
与年龄相关的伤口愈合受损是一个重大的健康负担，会导致老年人出现相当高的发病率和死亡率。受伤时，单核细胞迁移至受损部位并分化为组织驻留巨噬细胞，这对伤口修复至关重要。为了使炎症反应得到适当消退，巨噬细胞分化为两种不同的表型，即经典活化的促炎巨噬细胞和交替活化的抗炎巨噬细胞。促炎巨噬细胞通常与促炎事件相关，而抗炎巨噬细胞则已知具有促进再生的作用。与年龄相关的伤口修复延迟通常归因于男女局部和全身雌激素水平随年龄增长而下降。然而，尽管雌激素在伤口愈合中的抗炎作用已有充分记录，但雌激素的作用以及雌激素受体（ERs）在巨噬细胞极化中的参与至今很少受到关注。为了研究雌激素和ERs对巨噬细胞极化的影响，在用脂多糖/干扰素-γ或白细胞介素-4/白细胞介素-13刺激以产生促炎或抗炎巨噬细胞之前，将单核细胞衍生的巨噬细胞用雌激素、ER-α激动剂/拮抗剂或ER-β激动剂/拮抗剂进行预处理。我们的研究结果证实，雌激素可能通过ER-α信号通路促进巨噬细胞的交替活化。用PPT等药物选择性靶向ER-α可能会导致开发新的疗法来治疗受损伤口中的过度炎症。
