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Deletion of c-FLIP from CD11b^hi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis.

ABSTRACT: Idiopathic pulmonary fibrosis is a progressive lung disease with complex pathophysiology and fatal prognosis. Macrophages (MΦ) contribute to the development of lung fibrosis; however, the underlying mechanisms and specific MΦ subsets involved remain unclear. During lung injury, two subsets of lung MΦ coexist: Siglec-F^hi resident alveolar MΦ and a mixed population of CD11b^hi MΦ 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-1β-converting enzyme-inhibitory protein (c-FLIP) to CD11b^hi MΦ. Upon loss of c-FLIP, CD11b^hi MΦ became susceptible to cell death. Using this system, we were able to show that eliminating CD11b^hi MΦ present 7-14 days after bleomycin injury was sufficient to protect mice from fibrosis. RNA-seq analysis of lung MΦ present during this time showed that CD11b^hi MΦ, but not Siglec-F^hi MΦ, expressed high levels of profibrotic chemokines and growth factors. Human MΦ from patients with idiopathic pulmonary fibrosis expressed many of the same profibrotic chemokines identified in murine CD11b^hi MΦ. Elimination of monocyte-derived MΦ 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 MΦ may be pharmacologically targeted.

SUBMITTER: McCubbrey AL

PROVIDER: S-EPMC5941310 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-? (TGF-?) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30?IU) and the development of pulmonary fibrosis was assessed. Pro and active forms of matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Lung fibrosis was determined by collagen subtype-specific gene expression, hydroxyproline concentration, and histological assessment. Alveolar TGF-? activation was measured using bronchoalveolar lavage cell pSmad2 levels and global TGF-? activity was assessed by pSmad2 immunohistochemistry. The active-MMP-9 to pro-MMP-9 ratio was significantly increased in Slpi(-/-) animals compared with wild-type animals, demonstrating enhanced metalloproteinase activity. Wild-type animals showed an increase in TGF-? activation following bleomycin, with a progressive and sustained increase in collagen type I, alpha 1 (Col1?1), III, alpha 1(Col3?1), IV, alpha 1(Col4?1) mRNA expression, and a significant increase in total lung collagen 28 days post bleomycin. In contrast Slpi(-/-) mice showed no significant increase of alveolar TGF-? activity following bleomycin, above their already elevated levels, although global TGF-? activity did increase. Slpi(-/-) mice had impaired collagen gene expression but animals demonstrated minimal reduction in lung fibrosis compared with wild-type animals. These data suggest that enhanced proteolysis does not further enhance TGF-? activation, and inhibits sustained Col1?1, Col3?1, and Col4?1 gene expression following lung injury. However, these changes do not prevent the development of lung fibrosis. Overall, these data suggest that the absence of Slpi does not markedly modify the development of lung fibrosis following bleomycin-induced lung injury.

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Deletion of c-FLIP from CD11b^hi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis.

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Dataset Information

Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Deletion of c-FLIP from CD11b^hi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis.