axis regulates M2 macrophage polarization and immunosuppression in mycobacterium tuberculosis.

[BACKGROUND] Mycobacterium tuberculosis (MTB) evades host immunity and maintains chronic infection, in part by reprogramming macrophage function. The chemokine and its receptor play 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 of antagonists and knockdown 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 by antagonists. At the cellular level, H37Ra upregulated expression, 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] The axis promotes M2-type macrophage polarization, suppresses apoptosis, and enhances immunosuppressive signaling in the context of H37Ra infection. Targeting may provide a promising strategy to reverse immune evasion and restore host defense mechanisms during MTB infection.