Misharin Alexander V, Morales-Nebreda Luisa, Reyfman Paul A, Cuda Carla M, Walter James M, McQuattie-Pimentel Alexandra C, Chen Ching-I, Anekalla Kishore R, Joshi Nikita, Williams Kinola J N, Abdala-Valencia Hiam, Yacoub Tyrone J, Chi Monica, Chiu Stephen, Gonzalez-Gonzalez Francisco J, Gates Khalilah, Lam Anna P, Nicholson Trevor T, Homan Philip J, Soberanes Saul, Dominguez Salina, Morgan Vince K, Saber Rana, Shaffer Alexander, Hinchcliff Monique, Marshall Stacy A, Bharat Ankit, Berdnikovs Sergejs, Bhorade Sangeeta M, Bartom Elizabeth T, Morimoto Richard I, Balch William E, Sznajder Jacob I, Chandel Navdeep S, Mutlu Gökhan M, Jain Manu, Gottardi Cara J, Singer Benjamin D, Ridge Karen M, Bagheri Neda, Shilatifard Ali, Budinger G R Scott, Perlman Harris
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.
J Exp Med. 2017 Aug 7;214(8):2387-2404. doi: 10.1084/jem.20162152. Epub 2017 Jul 10.
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.
关于单核细胞和组织驻留巨噬细胞在肺纤维化发展中的相对重要性，人们了解甚少。我们发现，单核细胞衍生的肺泡巨噬细胞募集到肺后进行特异性基因缺失可改善肺纤维化，而组织驻留肺泡巨噬细胞对纤维化无影响。通过对流式分选细胞进行转录组分析，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持续进行。在纤维化阶段，单核细胞衍生的肺泡巨噬细胞在促纤维化基因表达方面与组织驻留肺泡巨噬细胞有显著差异。纤维化消退后，一群单核细胞衍生的肺泡巨噬细胞在肺中持续存在了一年，在此期间它们变得越来越类似于组织驻留肺泡巨噬细胞。与正常肺相比，纤维化人肺肺泡巨噬细胞中，小鼠单核细胞衍生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类同源物上调。我们的研究结果表明，在肺内选择性靶向肺泡巨噬细胞分化可能改善纤维化，而不会产生与整体单核细胞或组织驻留肺泡巨噬细胞耗竭相关的不良后果。
