在伤口修复过程中,STAT3/SETDB2 轴决定了巨噬细胞中 NF-κB 介导的炎症。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Kevin D Mangum, Aaron denDekker, Qinmengge Li, Lam C Tsoi, Amrita D Joshi, William J Melvin, Sonya J Wolf, Jadie Y Moon, Christopher O Audu, James Shadiow, Andrea T Obi, Rachael Wasikowski, Emily C Barrett, Tyler M Bauer, Kylie Boyer, Zara Ahmed, Frank M Davis, Johann Gudjonsson, Katherine A Gallagher
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引用次数: 0

摘要

组织损伤后巨噬细胞从炎症表型向修复表型的转变是由调控炎症基因表达的表观遗传酶控制的。我们之前发现巨噬细胞中的组蛋白甲基转移酶 SETDB2 通过抑制 NF-κB 介导的炎症来推动组织修复。对从骨髓细胞中缺乏 SETDB2 的小鼠体内分离出的伤口巨噬细胞进行 ATAC-Seq 和 RNA-Seq 的互补分析发现,SETDB2 通过抑制 NF-κB 依赖性基因启动子的染色质可及性来抑制炎症基因程序。我们发现,巨噬细胞中 SETDB2 的表达需要 STAT3,但矛盾的是,STAT3 也是 SETDB2 的结合伙伴,它通过抑制 SETDB2 与 NF-κB 成分 RELA 的相互作用来抑制 SETDB2 的活性,从而导致 RELA/NF-κB 介导的炎症基因表达增加。此外,对 STAT3 缺失小鼠伤口巨噬细胞的 RNA-Seq 研究也证实了这一点,并发现 STAT3 和 SETDB2 在转录上核心化了重叠基因。最后,在糖尿病伤口巨噬细胞中,STAT3 的表达和 STAT3/SETDB2 的结合都有所增加。我们发现了一种新的 STAT3/SETDB2 轴,我们认为它能在组织修复过程中调节巨噬细胞表型,并可能成为糖尿病伤口不愈合的重要治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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