Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.
Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.
复制标题
DOI：
10.1084/jem.20162152
复制
发表时间：
2017-08-07
期刊：
影响因子：
--
通讯作者：
Perlman H
中科院分区：
文献类型：
--
作者：
Misharin AV;Morales-Nebreda L;Reyfman PA;Cuda CM;Walter JM;McQuattie-Pimentel AC;Chen CI;Anekalla KR;Joshi N;Williams KJN;Abdala-Valencia H;Yacoub TJ;Chi M;Chiu S;Gonzalez-Gonzalez FJ;Gates K;Lam AP;Nicholson TT;Homan PJ;Soberanes S;Dominguez S;Morgan VK;Saber R;Shaffer A;Hinchcliff M;Marshall SA;Bharat A;Berdnikovs S;Bhorade SM;Bartom ET;Morimoto RI;Balch WE;Sznajder JI;Chandel NS;Mutlu GM;Jain M;Gottardi CJ;Singer BD;Ridge KM;Bagheri N;Shilatifard A;Budinger GRS;Perlman H
Misharin等人阐明了单核细胞来源的肺泡巨噬细胞在肺纤维化过程中的命运和功能。这些细胞在整个生命周期中持续存在，富含促纤维化基因的表达，它们的基因消融改善了肺纤维化的发展。关于单核细胞和组织巨噬细胞在肺纤维化发展中的相对重要性，我们知之甚少。我们发现，单核细胞来源的肺泡巨噬细胞募集到肺后，特异性基因缺失可改善肺纤维化，而组织驻留的肺泡巨噬细胞不会导致纤维化。利用流式细胞的转录组学分析，我们发现单核细胞向肺泡巨噬细胞的分化在纤维化及其消退过程中不断展开。在纤维化阶段，单核细胞来源的肺泡巨噬细胞与组织驻留的肺泡巨噬细胞在促纤维化基因的表达上存在显著差异。单核细胞来源的肺泡巨噬细胞在纤维化消退后在肺中持续存在一年，在那里它们变得越来越类似于组织内的肺泡巨噬细胞。小鼠单核细胞来源的肺泡巨噬细胞在纤维化过程中表达的促纤维化基因的人同源物在纤维化的人肺泡巨噬细胞中与正常肺相比上调。我们的研究结果表明，选择性靶向肺内肺泡巨噬细胞分化可以改善纤维化，而不会产生与全局单核细胞或组织内肺泡巨噬细胞耗竭相关的不良后果。
Misharin et al. elucidate the fate and function of monocyte-derived alveolar macrophages during the course of pulmonary fibrosis. These cells persisted throughout the life span, were enriched for the expression of profibrotic genes, and their genetic ablation ameliorated development of pulmonary fibrosis. Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.
登录
查看更多内容
影响因子：
4.3
作者：
Eden E;Lipson D;Yogev S;Yakhini Z
通讯作者：
Yakhini Z
影响因子：
3.7
作者：
Chevaleyre J;Duchez P;Rodriguez L;Vlaski M;Villacreces A;Conrad-Lapostolle V;Praloran V;Ivanovic Z;Brunet de la Grange P
通讯作者：
Brunet de la Grange P
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
6
作者：
Aschner, Yael;Khalifah, Anthony P.;Downey, Gregory P.
通讯作者：
Downey, Gregory P.
影响因子：
4
作者：
Chan, Matilda F.;Li, Jing;Werb, Zena
通讯作者：
Werb, Zena