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

  • Cell Rep. 2025 Jan 18;44(2):115220. doi: 10.1016/j.celrep.2024.115220.
Li Liu  1 ,  Pei Wu  1 ,  Yuqi Wei  2 ,  Meng Lu  1 ,  Haiyan Ge  3 ,  Ping Wang  1 ,  Jianlong Sun  1 ,  Tiffany Horng  2 ,  Xiucheng Liu  4 ,  Xiaoyong Shen  5 ,  Lingyun Sun  6 ,  Ying Xi  7
Affiliations
  • 1. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3. Department of Pulmonary and Critical Care Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
  • 4. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: [email protected].
  • 5. Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China. Electronic address: [email protected].
  • 6. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: [email protected].
  • 7. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected].
PMID: 39827460 DOI: 10.1016/j.celrep.2024.115220
Abstract

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.

Keywords
CP: Immunology; alveolar regeneration; lung fibrosis; macrophage-fibroblast crosstalk.
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