2. Academic Validation
  3. 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

  • 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

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: xiucheng_liu@outlook.com.
  • 5 Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China. Electronic address: xiaoyongshen@fudan.edu.cn.
  • 6 Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address: lingyunsun@nju.edu.cn.
  • 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: xiying@shanghaitech.edu.cn.
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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