TET3-overexpressing macrophages promote endometriosis.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Haining Lv, Beibei Liu, Yangyang Dai, Feng Li, Stefania Bellone, Yuping Zhou, Ramanaiah Mamillapalli, Dejian Zhao, Muthukumaran Venkatachalapathy, Yali Hu, Gordon G Carmichael, Da Li, Hugh S Taylor, Yingqun Huang
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Abstract

Endometriosis is a debilitating, chronic inflammatory disease affecting approximately 10% of reproductive-age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we report identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We show that factors from the disease microenvironment upregulated TET3 expression, transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated proinflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival and hence were vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation in both human and mouse macrophages. This degradation was dependent on a von Hippel-Lindau (VHL) E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.

TET3表达过高的巨噬细胞会促进子宫内膜异位症。
子宫内膜异位症是一种使人衰弱的慢性炎症性疾病,影响着全球约 10% 的育龄妇女,且无法治愈。虽然巨噬细胞与子宫内膜异位症的病理生理学有着内在联系,但由于巨噬细胞的高度异质性,以及这些疾病相关巨噬细胞(DAMs)既可以是致病性的,也可以是保护性的,因此以它们为治疗靶点极具挑战性。在此,我们报告了在人类子宫内膜异位症病灶中发现了以 TET3 过表达为特征的致病性巨噬细胞。我们发现,疾病微环境因素上调了 TET3 的表达,使巨噬细胞转化为致病性 DAMs。TET3 的过度表达通过抑制 let-7 miRNA 表达的反馈机制刺激了促炎细胞因子的产生。值得注意的是,这些细胞依赖于 TET3 的过表达而存活,因此很容易受到 TET3 敲除的影响。我们证实,合成胞嘧啶衍生物 Bobcat339 能在人和小鼠巨噬细胞中触发 TET3 降解。这种降解依赖于一种 VHL E3 泛素连接酶,它的表达在 TET3 表达过高的巨噬细胞中也会上调。此外,通过髓系特异性 Tet3 消融或使用 Bobcat339 来消耗 TET3 表达过高的巨噬细胞,可有效抑制小鼠子宫内膜异位症的进展。我们的研究结果表明,TET3表达过高的巨噬细胞是子宫内膜异位症的主要致病因素,也是有吸引力的治疗靶点。我们的研究结果可能也适用于其他慢性炎症性疾病,因为DAMs在这些疾病中发挥着重要作用。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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