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

Am J Respir Cell Mol Biol. 2018 Jan;58(1):66-78. doi: 10.1165/rcmb.2017-0154OC.

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-Fhi resident alveolar MΦ and a mixed population of CD11bhi 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 CD11bhi MΦ. Upon loss of c-FLIP, CD11bhi MΦ became susceptible to cell death. Using this system, we were able to show that eliminating CD11bhi 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 CD11bhi MΦ, but not Siglec-Fhi 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 CD11bhi 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.

Keywords: IPF; RNA-seq; c-FLIP; fibrosis; macrophage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bleomycin / adverse effects*
  • Bleomycin / pharmacology
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • CD11 Antigens / genetics
  • CD11 Antigens / metabolism*
  • Female
  • Gene Deletion*
  • Humans
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD11 Antigens
  • Cflar protein, mouse
  • Bleomycin