Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis
Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis
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DOI：
10.1165/rcmb.2017-0154oc
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发表时间：
2018-01-01
影响因子：
6.4
通讯作者：
Janssen, William J.
中科院分区：
文献类型：
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作者：
McCubbrey, Alexandra L.;Barthel, Lea;Janssen, William J.
特发性肺纤维化是一种进行性肺部疾病，具有复杂的病理生理学和致命的预后。巨噬细胞 (M Phi) 有助于肺纤维化的发展；然而，潜在的机制和涉及的特定 M Phi 子集仍不清楚。在肺损伤期间，肺 M Phi 的两个子集共存：Siglec-F-hi 常驻肺泡 M Phi 和主要由迁移单核细胞成熟的 CD11b(hi) M Phi 混合群体。使用由人 CD68 启动子片段驱动的新型诱导转基因系统，我们将抗凋亡蛋白细胞 FADD 样 IL-1 β 转换酶抑制蛋白 (c-FLIP) 的缺失靶向删除为 CD11b(hi) M Phi。 c-FLIP 丢失后，CD11b(hi) M Phi 变得容易细胞死亡。使用该系统，我们能够证明消除博莱霉素损伤后 7-14 天存在的 CD11b(hi) M Phi 足以保护小鼠免受纤维化。在此期间对肺 M Phi 进行的 RNA-seq 分析表明，CD11b(hi) M Phi（而非 Siglec-F-hi M Phi）表达高水平的促纤维化趋化因子和生长因子。来自特发性肺纤维化患者的人 M Phi 表达许多与小鼠 CD11b(hi) M Phi 中鉴定的相同的促纤维化趋化因子。消除单核细胞来源的 M Phi 可能有助于治疗纤维化。我们将 c-FLIP 和相关的外源性细胞死亡程序确定为潜在的途径，通过该途径这些促纤维化 M Phi 可以成为药物靶点。
Idiopathic pulmonary fibrosis is a progressive lung disease with complex pathophysiology and fatal prognosis. Macrophages (M Phi) contribute to the development of lung fibrosis; however, the underlying mechanisms and specific M Phi subsets involved remain unclear. During lung injury, two subsets of lung M Phi coexist: Siglec-F-hi resident alveolar M Phi and a mixed population of CD11b(hi) M Phi that primarily mature from immigrating monocytes. Using a novel inducible transgenic system driven by a fragment of the human CD68 promoter, we targeted deletion of the antiapoptotic protein cellular FADD-like IL-1 beta-converting enzyme-inhibitory protein (c-FLIP) to CD11b(hi) M Phi. Upon loss of c-FLIP, CD11b(hi) M Phi became susceptible to cell death. Using this system, we were able to show that eliminating CD11b(hi) M Phi present 7-14 days after bleomycin injury was sufficient to protect mice from fibrosis. RNA-seq analysis of lung M Phi present during this time showed that CD11b(hi) M Phi, but not Siglec-F-hi M Phi, expressed high levels of profibrotic chemokines and growth factors. Human M Phi from patients with idiopathic pulmonary fibrosis expressed many of the same profibrotic chemokines identified in murine CD11b(hi) M Phi. Elimination of monocyte-derived M Phi may help in the treatment of fibrosis. We identify c-FLIP and the associated extrinsic cell death program as a potential pathway through which these profibrotic M Phi may be pharmacologically targeted.