| First Author | McCubbrey AL | Year | 2018 |
| Journal | Am J Respir Cell Mol Biol | Volume | 58 |
| Issue | 1 | Pages | 66-78 |
| PubMed ID | 28850249 | Mgi Jnum | J:269228 |
| Mgi Id | MGI:6272140 | Doi | 10.1165/rcmb.2017-0154OC |
| Citation | McCubbrey AL, et al. (2018) Deletion of c-FLIP from CD11b(hi) Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis. Am J Respir Cell Mol Biol 58(1):66-78 |
| abstractText | Idiopathic pulmonary fibrosis is a progressive lung disease with complex pathophysiology and fatal prognosis. Macrophages (MPhi) contribute to the development of lung fibrosis; however, the underlying mechanisms and specific MPhi subsets involved remain unclear. During lung injury, two subsets of lung MPhi coexist: Siglec-F(hi) resident alveolar MPhi and a mixed population of CD11b(hi) MPhi 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-1beta-converting enzyme-inhibitory protein (c-FLIP) to CD11b(hi) MPhi. Upon loss of c-FLIP, CD11b(hi) MPhi became susceptible to cell death. Using this system, we were able to show that eliminating CD11b(hi) MPhi present 7-14 days after bleomycin injury was sufficient to protect mice from fibrosis. RNA-seq analysis of lung MPhi present during this time showed that CD11b(hi) MPhi, but not Siglec-F(hi) MPhi, expressed high levels of profibrotic chemokines and growth factors. Human MPhi from patients with idiopathic pulmonary fibrosis expressed many of the same profibrotic chemokines identified in murine CD11b(hi) MPhi. Elimination of monocyte-derived MPhi 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 MPhi may be pharmacologically targeted. |
