MCP-1/CCR2 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 MCP-1 and its receptor CCR2 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 CCR2 -related gene expression changes and enriched pathways. In addition, the effects of CCR2 antagonists and MCP-1 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 CCR2 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 CCR2 -dependent genes involved in immune response and apoptosis, including Trim30 , Fas , and PD-1 , which were reversed by CCR2 antagonists. At the cellular level, H37Ra upregulated MCP-1 expression, promoting M2 polarization. MCP-1 Knockdown enhanced macrophage apoptosis, reversed M2 polarization, and suppressed immunosuppressive signaling. Additionally, MCP-1 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 MCP-1/CCR2 axis promotes M2-type macrophage polarization, suppresses apoptosis, and enhances immunosuppressive signaling in the context of H37Ra infection. Targeting CCR2/MCP-1 may provide a promising strategy to reverse immune evasion and restore host defense mechanisms during MTB infection.