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IL-4极化巨噬细胞的表观遗传状态使炎症顺循环扩张
作者:小柯机器人 发布时间:2022/11/5 17:12:48

匈牙利德布勒森大学Laszlo Nagy团队近期取得重要工作进展,他们研究发现IL-4极化巨噬细胞的表观遗传状态使炎症顺循环扩张并延长对TLR配体的协同反应。该项研究成果2022年11月1日在线发表于《免疫学》杂志上。

研究人员发现IL-4极化的巨噬细胞在暴露于脂多糖(LPS)后建立了一个高炎症基因表达程序。研究人员称这种现象为扩展协同作用,得到了IL-4导向的表观基因组重塑、LPS激活的NF-κB-p65顺循环扩张和增强子活性增加的支持。EGR2转录因子以巨噬细胞亚型特异性的方式促成了扩展的协同作用。因此,先前交替极化的巨噬细胞在体外和体内小鼠Th2细胞型气道炎症模型中,在LPS暴露时产生了更多的免疫调节因子。结果表明,IL-4诱导的表观遗传重编程导致炎症对TLR激活的高反应性,加速导致肺部病变。

据介绍,事先接触到微环境信号可能从根本上改变巨噬细胞对后续刺激的反应。辅助性T细胞-2(Th2)型细胞因子白细胞介素-4(IL-4)和Toll样受体(TLR)配体激活的转录程序相互拮抗,并且它们之间没有发现明显的趋同性。

附:英文原文

Title: The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands

Author: Zsolt Czimmerer, Laszlo Halasz, Bence Daniel, Zsofia Varga, Krisztian Bene, Apolka Domokos, Marten Hoeksema, Zeyang Shen, Wilhelm K. Berger, Timea Cseh, Karoly Jambrovics, Zsuzsanna Kolostyak, Ferenc Fenyvesi, Judit Varadi, Szilard Poliska, Gyorgy Hajas, Istvan Szatmari, Christopher K. Glass, Attila Bacsi, Laszlo Nagy

Issue&Volume: 2022-11-01

Abstract: Prior exposure to microenvironmental signals could fundamentally change the response of macrophages to subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, and no remarkable convergence has been identified between them. In contrast, here, we show that IL-4-polarized macrophages established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS) exposure. This phenomenon, which we termed extended synergy, was supported by IL-4-directed epigenomic remodeling, LPS-activated NF-κB-p65 cistrome expansion, and increased enhancer activity. The EGR2 transcription factor contributed to the extended synergy in a macrophage-subtype-specific manner. Consequently, the previously alternatively polarized macrophages produced increased amounts of immune-modulatory factors both in vitro and in vivo in a murine Th2 cell-type airway inflammation model upon LPS exposure. Our findings establish that IL-4-induced epigenetic reprogramming is responsible for the development of inflammatory hyperresponsiveness to TLR activation and contributes to lung pathologies.

DOI: 10.1016/j.immuni.2022.10.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00545-3

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx