YY1-activated LINC00926 promotes the survival of mycobacteria and regulates inflammatory response in Mycobacterium tuberculosis-infected macrophages.

Tuberculosis, caused by infection with Mycobacterium tuberculosis (M.tb), remains a major global public health challenge. Long noncoding RNAs (lncRNAs) have emerged as pivotal regulators of immune response during infection. Notably, lncRNA LINC00926 is upregulated in peripheral blood mononuclear cells from tuberculosis patients. This study aimed to investigate the functional role of LINC00926 and its underlying mechanisms in M.tb-infected macrophages. Our RT-qPCR analysis revealed that M.tb infection time- and dose-dependently upregulated LINC00926 expression in THP-1 macrophages. Then, macrophages were transfected with LINC00926 short hairpin RNAs for knockdown assays, followed by infection with the M.tb H37Rv strain. Functional experiments were conducted to evaluate LINC00926's functional roles. RT-qPCR and enzyme-linked immunosorbent assay (ELISA) showed that LINC00926 knockdown suppressed the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in macrophages. Flow cytometry analysis and western blotting demonstrated that LINC00926 knockdown reduced macrophage apoptosis and enhanced autophagic activity, as evidenced by an increased LC3-II/I ratio, elevated Beclin1 levels, and decreased p62 levels. A colony-forming unit assay revealed the inhibitory effect of LINC00926 knockdown on M.tb survival in infected macrophages. Bioinformatics analysis and experimental validation via chromatin immunoprecipitation and luciferase reporter assays demonstrated that YY1 transcriptionally activated LINC00926 by binding to its promoter region, and LINC00926 competitively interacted with miR-106a-5p to upregulate STAT3. Moreover, miR-106a-5p inhibition restored the effects of LINC00926 knockdown on inflammation, apoptosis, and bacterial survival in M.tb-infected macrophages. Overall, YY1-mediated activation of LINC00926 promotes mycobacterial survival and exacerbates inflammatory responses in M.tb-infected macrophages by targeting miR-106a-5p.