Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease.
Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease.
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气道巨噬细胞的表观遗传重编程促进粘膜阻塞性肺病的极化和炎症。
DOI：
10.1038/s41467-021-26777-9
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发表时间：
2021-11-11
影响因子：
16.6
通讯作者：
Mall MA
中科院分区：
文献类型：
--
作者：
Hey J;Paulsen M;Toth R;Weichenhan D;Butz S;Schatterny J;Liebers R;Lutsik P;Plass C;Mall MA
囊性纤维化和慢性阻塞性肺病等肺部疾病的特征是粘液阻塞和慢性气道炎症，但其机制联系仍知之甚少。在这里，我们重点关注粘液抑制气道微环境对气道巨噬细胞（AM）表观遗传重编程以及由此产生的转录组和表型变化的作用。使用粘液阻塞性肺病（Scnn1b 转基因）小鼠模型，我们确定了参与炎症反应和巨噬细胞极化的表观遗传控制、差异调节途径和转录因子。从功能上讲，来自 Scnn1b 转基因小鼠的 AM 减少了胞吞作用和吞噬作用，以及脂多糖攻击时的过度炎症反应，这是通过增强 Irf1 功能和表达介导的。用天然粘液对野生型 AM 进行体外刺激会损害胞吞作用和吞噬能力。此外，粘液诱导基因表达变化，与 Scnn1b 转基因小鼠 AM 中观察到的变化相当。我们的数据表明，粘膜停滞会诱导 AM 的表观遗传重编程，从而导致有利于组织损伤和疾病进展的变化。针对这些改变的 AM 可能支持粘液阻塞性肺病患者的治疗方法。粘液阻塞性肺病的特征是气道巨噬细胞 (AM) 群体可能发生表观遗传变化。在这里，作者使用小鼠模型展示了 AM 的表观遗传改变，以及 LPS 反应、吞噬作用和胞吞作用的变化，类似于体外粘液培养。
Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases. Muco-obstructive lung diseases are characterised by airway macrophage (AM) populations which may have epigenetic changes. Here using a mouse model the authors show epigenetic alteration of AMs with changes in LPS response, phagocytosis and efferocytosis similar to culture with mucus in vitro.
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DOI：
10.1056/nejmra0910061
发表时间：
2010-12-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Fahy JV;Dickey BF
通讯作者：
Dickey BF
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
16.6
作者：
Angelidis, Ilias;Simon, Lukas M.;Schiller, Herbert B.
通讯作者：
Schiller, Herbert B.
影响因子：
13.5
作者：
Edwards MR;Bartlett NW;Clarke D;Birrell M;Belvisi M;Johnston SL
通讯作者：
Johnston SL
影响因子：
24.3
作者：
Fricker, Michael;Gibson, Peter G.
通讯作者：
Gibson, Peter G.