Abstract
Extracellular matrix production by pleural mesothelial cells in response to Mycobacterium tuberculosis contributes to tuberculous fibrosis. NOX4 is involved in the pathogenesis of tuberculous fibrosis. In this study, we evaluated whether NOX4 gene-targeting microRNAs showed protective effects in tuberculosis fibrosis. TargetScan prediction software was used to identify candidate microRNAs that bind the 3′ UTRs of NOX4, and microRNA-148a (miR-148a) was selected as the best miRNA candidate. A repressed and forced expression assay in Met5A cells was performed to investigate the causal relationship between miR-148a and NOX4. The role of miR-148a in tuberculous pleural fibrosis was studied using a murine model of Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection. Heat-killed M. tuberculosis (HKMT) induces NOX4 and POLDIP2 expression. We demonstrated the inhibitory effect of miR-148a on NOX4 and POLDIP2 expression. The increased expression of miR-148a suppressed HKMT-induced collagen-1A synthesis in PMC cells. In the BCG pleurisy model, miR-148a significantly reduced fibrogenesis and epithelial mesenchymal transition. High levels of miR-148a in tuberculous pleural effusion can be interpreted as a self-limiting homeostatic response. Our data indicate that miR-148a may protect against tuberculous pleural fibrosis by regulating NOX4 and POLDIP2.
Highlights
Accepted: 4 March 2022Tuberculosis (TB) is a global public health problem responsible for 9.9 million incident cases [1]
This is associated with excessive deposition of the extracellular matrix (ECM), stiffness, and parenchymal scarring in tuberculous fibrosis [5,6]
MiR-148a was identified as a novel miRNA involved in tuberculous fibrosis
Summary
Tuberculosis (TB) is a global public health problem responsible for 9.9 million incident cases [1]. TB mortality has reduced, and 85% (66 million cases) of the treated patients survive [1]. Approximately half of the TB survivors complain of chronic pulmonary dysfunction and reduced quality of life despite microbiological cures [2–4]. This is associated with excessive deposition of the extracellular matrix (ECM), stiffness, and parenchymal scarring in tuberculous fibrosis [5,6]. Residual distortion of the lung architecture resulting in pulmonary dysfunction depends on the degree to which the ECM is degraded [7]. Investigating the underlying immunological mechanism involving tuberculous fibrosis could help identify therapeutic targets
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