Deletion of c-FLIP from CD11b(hi) Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis

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.