Fibroblast-derived CXCL14 aggravates crystalline silica-induced pulmonary fibrosis by mediating polarization and recruitment of interstitial macrophages.

Yichuan You, Haoyang Yuan, Hui Min, Chao Li, Jie Chen

Journal of hazardous materials 2023 Oct 15

filter terms:

Exposure to crystalline silica (CS) particles in worksites and dwellings can lead to silicosis due to excessive fibroblast activation. Considering their immuno-regulatory activities, the contribution of pulmonary fibroblasts in the progression of silicosis has not been thoroughly characterized. Here, we demonstrate that exposure of the lung to CS particles leads to the upregulation of fibroblast-derived C-X-C motif chemokine ligand 14 (CXCL14). By employing an in vitro co-culture system, we demonstrated activated fibroblasts recruited bone marrow-derived macrophages (BMDMs) and favored alternative macrophage polarization (M2) mediated by CXCL14. Furthermore, in vivo studies echoed that systemic CXCL14 neutralizing or fibroblast-specific Cxcl14 knockout proved CXCL14 was indispensable for the recruitment and phenotype alteration of lung macrophages, especially interstitial macrophages (IMs), under stimulation by CS particles. Mechanistically, we showed that GLI2 and p21-mediated cellular senescence were mediators of CXCL14 production following CS exposure. Accordingly, GLI2 blockage and countering cellular senescence by reviving PINK1-mediated mitophagy may be efficient strategies to reduce CXCL14 expression in activated fibroblasts during silicosis. Our findings emphasize the immuno-regulatory function of fibroblasts in silicosis via CXCL14, providing intervention targets for CS-induced pulmonary fibrosis. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Yichuan You, Haoyang Yuan, Hui Min, Chao Li, Jie Chen. Fibroblast-derived CXCL14 aggravates crystalline silica-induced pulmonary fibrosis by mediating polarization and recruitment of interstitial macrophages. Journal of hazardous materials. 2023 Oct 15;460:132489