Silencing Mcl-1: A novel approach to modulate macrophage polarization in tuberculosis

This study investigated the effect of targeted silencing of myeloid cell leukemia-1 (Mcl-1) on the polarization of Mycobacterium tuberculosis-infected macrophages, both in vitro and in vivo. We also examined the associated organ lesions to clarify the potential of Mcl-1 silencing in preventing and treating tuberculosis.

Using the CIBERSORT algorithm, we analyzed the immune cell infiltration patterns in 100 cases of pulmonary tuberculosis and 79 cases of latent infection from the integrated cohorts (GSE34608 and GSE83456). Furthermore, the expression levels, clinical decision utility, and diagnostic value of Mcl-1 in TB patients were evaluated. Based on these results, Mcl-1 was silenced via RNAi in BCG-infected macrophages and murine models. Macrophage polarization changes and tissue damage were assessed using Western blotting, ELISA, RT-PCR, immunofluorescence, H&E staining, and immunohistochemistry.

The results of the immune infiltration analysis indicate that both M1 and M2 macrophages are elevated following infection with Mycobacterium tuberculosis. Notably, Mcl-1 expression was significantly upregulated in the TB group compared to controls, demonstrating a high diagnostic value (AUC = 0.745) and positive net clinical benefit. Both cell-based and animal models reveal that silencing Mcl-1 modulates macrophage polarization during infection. Compared to the BCG-treated group, markers and pro-inflammatory cytokines associated with M1 macrophages initially increased and subsequently decreased, whereas markers and anti-inflammatory cytokines related to M2 macrophages first declined and then rose. Concurrently, mice exhibited reduced organ indices and restoration of lung tissue architecture.

Mcl-1 knockdown modulates macrophage polarization in BCG infection, rebalancing the M1/M2 ratio and enhancing Mycobacterium tuberculosis clearance while reducing inflammation and protecting host tissues.