TWEAK-Fn14 signaling protects mice from pulmonary fibrosis by inhibiting fibroblast activation and recruiting pro-regenerative macrophages

TWEAK-Fn14 signaling protects mice from pulmonary fibrosis by inhibiting fibroblast activation and recruiting pro-regenerative macrophages

Summary: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excess accumulation of the extracellular matrix (ECM). The role of macrophage-fibroblast crosstalk in lung fibrogenesis is incompletely understood. Here we found that fibroblast growth factor-inducible molecule 14...

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Main Authors: Li Liu, Pei Wu, Yuqi Wei, Meng Lu, Haiyan Ge, Ping Wang, Jianlong Sun, Tiffany Horng, Xiucheng Liu, Xiaoyong Shen, Lingyun Sun, Ying Xi
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:Cell Reports
Subjects:
CP: Immunology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124724015717
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Summary:Summary: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excess accumulation of the extracellular matrix (ECM). The role of macrophage-fibroblast crosstalk in lung fibrogenesis is incompletely understood. Here we found that fibroblast growth factor-inducible molecule 14 (Fn14), the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is highly induced in myofibroblasts in the lungs of IPF patients and the bleomycin-induced lung fibrosis model. TWEAK-Fn14 signaling inhibits fibroblast activation and ECM synthesis and induces chemokine expression to recruit monocytes/macrophages into the lung. Fn14 deficiency increases ECM production and impairs macrophage infiltration and differentiation, leading to exacerbated lung fibrosis and impaired alveolar regeneration in a bleomycin model. Interestingly, Fn14 deficiency diminishes an injury-induced SiglecF− CD11b− MHCIIlo intermediate macrophage (IntermM) subpopulation, which promotes alveolar type II (AT2) cell proliferation in organoid cultures. These results collectively demonstrate a protective role of TWEAK-Fn14 signaling in lung fibrosis, highlighting the complexities and multilayered regulation of macrophage-fibroblast crosstalk.
ISSN:2211-1247

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