2. Academic Validation
  3. Orderly Regulation of Macrophages and Fibroblasts by Axl in Bleomycin-Induced Pulmonary Fibrosis in Mice

Orderly Regulation of Macrophages and Fibroblasts by Axl in Bleomycin-Induced Pulmonary Fibrosis in Mice

  • J Cell Mol Med. 2025 Jan;29(1):e70321. doi: 10.1111/jcmm.70321.
Xinyu Zhao 1,  Yupeng Li 1,  Shengnan Yang 2 3 4,  Yicong Chen 5,  Kaiwei Wu 6,  Jing Geng 2 3,  Peipei Liu 7,  Zai Wang 2 3 8,  Huaping Dai 2 3,  Chen Wang 1
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital of Harbin Medical University, Heilongjiang, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
  • 3 National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.
  • 4 Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, China.
  • 5 Capital Medical University, Beijing, China.
  • 6 Peking Union Medical College, Beijing, China.
  • 7 Department of Medicine and Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • 8 Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
PMID: 39779468 DOI: 10.1111/jcmm.70321
Abstract

Pulmonary fibrosis is a pathological manifestation that occurs upon lung injury and subsequence aberrant repair with poor prognosis. However, current treatment is limited and does not distinguish different disease stages. Here, we aimed to study the differential functions of Axl, a receptor tyrosine kinase expressing on both macrophages and fibroblasts, in the whole course of pulmonary fibrosis. We used mice with Axl total knockout, conditionally knockout in macrophages or fibroblasts, or treating with Axl inhibitors in inflammation or fibrosis stages to examine the effect of temporary dysfunction of Axl on bleomycin (BLM)-induced pulmonary fibrosis. Primary bone marrow-derived monocytes and primary fibroblasts from mice were used for cell-type-specific studies. Lung tissue and plasma samples were collected from idiopathic pulmonary fibrosis (IPF) patients and healthy controls to assess the Axl levels. We found that Axl inhibited the M1 polarisation of macrophages; inhibition of Axl during acute phase exacerbated inflammatory response and subsequent pulmonary fibrosis. On the Other hand, Axl promoted the proliferation and invasion of the fibroblasts, partially by accelerating the focal adhesion turnover; inhibiting Axl during the fibrotic phase significantly alleviated pulmonary fibrosis. Consistently, phosphorylated Axl levels increased in fibrotic foci in the lung sample of IPF patients. In contrast, the soluble Axl (sAxl) level decreased in their plasma as compared to healthy controls. These results indicate that Axl may sequentially and differentially regulate macrophages and fibroblasts in acute and fibrosis phases, implying the necessity of a stage-specific treatment for pulmonary fibrosis. In addition, the activated Axl on fibroblasts may be reflected by the lowered plasma sAxl level, which may act as a biomarker for IPF. Trial Registration: ClinicalTrials.gov identifier: NCT03730337.

Keywords

Axl; fibroblast; lung injury; macrophage; pulmonary fibrosis.

Figures
Products