HMGB1 Upregulates MMP-1-Mediated Mesothelial-Mesenchymal Transition and Promotes Pleural Fibrosis in Tuberculous...

High-mobility group box 1 (HMGB1) has been implicated in matrix remodeling and fibrotic disorders; however, its role in tuberculosis (TB)-associated pleural fibrosis remains unknown. Pleural fluid levels of HMGB1 and matrix metalloproteinase-1 (MMP-1) in patients with TB pleural effusion (TBPE, n = 36) or transudative pleural effusion (TPE, n = 14) were measured. The effects of Mycobacterium tuberculosis H37Ra (MTBRa) on HMGB1 and MMP-1 expression and their effects on mesothelial-mesenchymal transition (MMT) in human pleural mesothelial cells (PMCs) were assessed. The levels of HMGB1 and MMP-1 were significantly higher in TBPE than in TPE. Elevated HMGB1 and MMP-1 levels in TBPE were positively correlated and both factors were significantly associated with post-TB residual pleural thickening (RPT), particularly in patients with RPT ≥ 10 mm. Colocalized expression of HMGB1 and MMP-1 was also observed in the pleural mesothelium of TBPE patients. MTBRa significantly induced HMGB1 expression in PMCs through activation of the JNK/AP-1 signaling pathway, leading to MMT, enhanced collagen synthesis, and upregulation of MMP-1. Furthermore, silencing of MMP-1 markedly attenuated HMGB1-triggered MMT response. Collectively, HMGB1 promotes pleural fibrogenesis through JNK/AP-1-dependent and MMP-1-mediated MMT, suggesting that targeting the HMGB1/MMP-1 axis may represent a potential therapeutic strategy for TB-related pleural fibrosis.