The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands.
The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands.
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DOI：
10.1016/j.immuni.2022.10.004
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发表时间：
2022-11-08
期刊：
影响因子：
32.4
通讯作者：
Nagy, Laszlo
中科院分区：
文献类型：
--
作者：
Czimmerer, Zsolt;Halasz, Laszlo;Daniel, Bence;Varga, Zsofia;Bene, Krisztian;Domokos, Apolka;Hoeksema, Marten;Shen, Zeyang;Berger, Wilhelm K.;Cseh, Timea;Jambrovics, Karoly;Kolostyak, Zsuzsanna;Fenyvesi, Ferenc;Varadi, Judit;Poliska, Szilard;Hajas, Gyorgy;Szatmari, Istvan;Glass, Christopher K.;Bacsi, Attila;Nagy, Laszlo
先前暴露于微环境信号可以从根本上改变巨噬细胞对后续刺激的反应。据信，T辅助细胞-2（Th 2）型细胞因子白介素-4（IL-4）和Toll样受体（TLR）配体激活的转录程序相互拮抗，并且在它们之间没有发现显著的收敛。相反，在这里，我们表明，IL-4极化的巨噬细胞建立了一个高炎症基因表达程序后，脂多糖（LPS）暴露。这种现象，我们称之为扩展的协同作用，得到了IL-4指导的表观基因组重塑，LPS激活的NF-κB-p65顺式组扩增和增强子活性增加的支持。EGR 2转录因子以巨噬细胞亚型特异性方式促进了扩展的协同作用。因此，先前交替极化的巨噬细胞产生的免疫调节因子在体外和体内的小鼠Th 2细胞型气道炎症模型LPS暴露后的量增加。我们的研究结果表明，IL-4诱导的表观遗传重编程是负责TLR激活的炎症高反应性的发展，并有助于肺部病理。IL-4和TLR配体之间的拮抗作用是预期的，并且在巨噬细胞中得到了很好的描述，但是它们的协同相互作用尚不清楚。Czimmerer等人证明，IL-4诱导的表观遗传重编程导致TLR激活的NF-κB-p65顺式组的大量扩增，开启了鼠和人巨噬细胞中不同的高炎症基因表达程序。
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. The antagonism between IL-4 and TLR ligands is expected and well described in macrophages, but their synergistic interactions are not understood. Czimmerer et al. demonstrate that IL-4-induced epigenetic reprogramming results in vast expansion of TLR-activated NF-κB-p65 cistrome, turning on a distinct hyperinflammatory gene expression program in murine and human macrophages.
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影响因子：
5.4
作者：
Bain CC;Louwe PA;Steers NJ;Bravo-Blas A;Hegarty LM;Pridans C;Milling SWF;MacDonald AS;Rückerl D;Jenkins SJ
通讯作者：
Jenkins SJ
DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
DOI：
10.1164/rccm.201304-0775oc
发表时间：
2013-11-15
影响因子：
24.7
作者：
Goleva, Elena;Jackson, Leisa P.;Leung, Donald Y. M.
通讯作者：
Leung, Donald Y. M.
影响因子：
8
作者：
du Plessis, N.;Kleynhans, L.;Walzl, G.
通讯作者：
Walzl, G.
影响因子：
10.5
作者：
Daniel B;Nagy G;Hah N;Horvath A;Czimmerer Z;Poliska S;Gyuris T;Keirsse J;Gysemans C;Van Ginderachter JA;Balint BL;Evans RM;Barta E;Nagy L
通讯作者：
Nagy L