Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.

The Epithelial-Immune Crosstalk in Pulmonary Fibrosis

“…Finally, HMGB1 can shape the immune contribution to fibrosis as it prompts macrophages to produce high levels of IL-1β, which could influence collagen deposition ( 98 ) and triggers the release of chemokines such as MCP-1/CCL2 by lung epithelial cells ( 99 ), a molecule known to enhance fibrocyte recruitment ( 100 ). Additionally, epithelial cells exposed to this molecule produce higher levels of TNF-α, which has been linked with TJ disassembly ( 101 ), fibroblast apoptosis ( 102 ) and EMT ( 103 , 104 ). The latter pro- and anti-fibrotic effect are mirrored by in vivo data, reporting both protective and promoting roles of this cytokine in lung fibrosis ( 105 , 106 ).…”