axis regulates M2 macrophage polarization and immunosuppression in mycobacterium tuberculosis.

Abstract

BACKGROUND: Mycobacterium tuberculosis (MTB) evades host immunity and maintains chronic infection, in part by reprogramming macrophage function. The chemokineand its receptorplay a key role in attracting monocytes and immunological modulation, but their exact involvement in MTB pathogenesis is unknown. METHODS: Using the H37Ra-infected mouse model, the expression of MTB virulence marker ESAT-6 and autophagy marker Beclin-1 was assessed. Transcriptome analysis was performed to identify-related gene expression changes and enriched pathways. In addition, the effects ofantagonists andknockdown on macrophage apoptosis, polarization, cytokine production, and immunosuppressive signaling were assessed using Quantitative real-time PCR, ELISA, flow cytometry, immunohistochemistry, immunofluorescence, and western blot. RESULTS: inhibition reduced ESAT-6 expression and restored Beclin-1 levels in lung tissue, alleviating inflammation and injury during late-stage infection. Transcriptomic profiling revealed that H37Ra infection activated-dependent genes involved in immune response and apoptosis, including,, and, which were reversed byantagonists. At the cellular level, H37Ra upregulatedexpression, promoting M2 polarization.Knockdown enhanced macrophage apoptosis, reversed M2 polarization, and suppressed immunosuppressive signaling. Additionally,knockdown increased TNF-α and IFN-γ levels, reduced TGF-β and IL-10 secretion, and oppositely regulated ESAT-6 and Beclin-1 expression. CONCLUSION: Theaxis promotes M2-type macrophage polarization, suppresses apoptosis, and enhances immunosuppressive signaling in the context of H37Ra infection. Targetingmay provide a promising strategy to reverse immune evasion and restore host defense mechanisms during MTB infection.