1144 - Mechanism Exploration of CXCL16-Positive Macrophages in Radiation-Induced Pulmonary Fibrosis and Fibroblast Behaviors
Presenter(s)
D. Xu1, X. Yuan1, and Y. Liu2; 1Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China, Wuhan, Hubei, China, 2Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Purpose/Objective(s): Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressively deteriorating interstitial lung disease that currently has no cure or reliable method of prediction. This study aims to investigate the mechanisms underlying the promotion of pulmonary fibrosis by CXCL16-positive macrophages and identify intervention targets.
Materials/Methods: Experimental mouse models of RIPF were established in wild-type mice, CXCL16 knockout mice, macrophage-specific CXCL16 knockout mice, and bone marrow chimeric mice. Meanwhile, CXCL16 monoclonal neutralizing antibodies (CXCL16 mAb) were developed and administered at different time points, complemented by detection of serum-related factors, tissue section staining, CT imaging and analysis. Additionally, the imaging effect of radionuclide-labeled CXCL16 antibodies in RIPF models was investigated via PET-CT.
Results: In vivo experiments showed that CXCL16 knockout or depletion of CXCL16-positive macrophages reduced the recruitment of macrophages and fibroblasts and inhibited fibroblast activation in the lungs. Administration of CXCL16 mAb was shown to alleviate RIPF. Furthermore, clinical evidence supported that serum CXCL16 could serve as a predictive biomarker for radiation-induced lung injury (RILI), and radionuclide-labeled CXCL16 antibodies enabled successful imaging in fibrotic lung tissues. Mechanistically, radiotherapy induces ATF3-mediated upregulation of CXCL16 expression. CXCL16 recruits macrophages and fibroblasts to the lungs and aggravates local inflammation. Meanwhile, CXCL16 binds to Latent transforming growth factor beta binding protein 1 (LTBP-1) and promotes the activation of Transforming growth factor beta 1 (TGF-ß1), which further enhances fibroblast activation and thereby promotes pulmonary fibrosis. These findings were validated in primary macrophages and multiple mouse models.
Conclusion: CXCL16-positive macrophages can promote RIPF progression. CXCL16 plays a key role in the prediction, diagnosis and treatment of RIPF, and CXCL16 monoclonal antibody alleviates pulmonary fibrosis via inhibiting fibroblast activation and recruitment through the ATF3/CXCL16/LTBP-1/TGF-ß1 pathway.