Exosomal microRNAs of tuberculous pleural effusion orchestrating TGF-β signaling mediate pleural fibrosis

Tuberculosis pleural effusion (TPE) accounts for 30 ~ 80% of all pleural effusions in developing countries and remains a major contributor to global morbidity and mortality. Although TPE is often absorbed after anti-tuberculosis treatment, approximately 60% of patients develop pleural thickening and pleural fibrosis. However, the underlying mechanisms of pleural fibrosis followed TPE remain poorly understood. In this study, firstly we found that exosomes isolated from TPE were associated with pleural fibrotic changes both in vivo and in vitro, accompanied by activation of the TGF-β signaling pathway. Disruption of exosomes or inhibition of exosome biogenesis attenuated these fibrotic responses. miRNA profiling revealed a distinct exosomal miRNA signature in TPE compared with transudative pleural effusion. Among these miRNAs, down-regulated miR-135b-5p was associated with increased SDCBP expression in pleural mesothelial cells (PMCs), while up-regulated miR-150-3p correlated with enhanced expression of the integrin ITGB6. In addition, miR-503-5p, miR-25-3p, miR-92a-3p and miR-424-3p were linked to reduced Smad7 and Smurf1 expression and decreased ubiquitination of TGF-βRI, collectively favoring TGF-β pathway. Together, these findings suggested that TPE-derived exosomal miRNAs converged on key regulatory nodes of TGF-β signaling and contributed to pleural fibrogenesis. This study provides mechanistic insight into post-tuberculous pleural fibrosis and supports exosomal miRNAs profile as a promising target for prevention and treatment of pleural fibrosis.