Mycobacterium tuberculosis reinforces M2 polarization of macrophages by activating glutamine metabolism.

BACKGROUND: Tuberculosis, a predominant health issue worldwide caused by Mycobacterium tuberculosis (Mtb), is refractory due to drug resistance. This study aims to explore whether Mtb reinforces M2 polarization of macrophages by modulating glutamine metabolism, thereby offering novel perspectives into its pathogenic mechanisms and potential therapeutic targets.

METHODS: This research established an in vivo model of C57BL/6 mice infected with Mtb H37Rv, and an in vitro infection model based on RAW264.7 macrophages. The expression of M2 polarization markers and activation of the key signaling molecule STAT6 were detected via flow cytometry, immunohistochemistry, RT-qPCR, Western blot (WB), and ELISA. The levels and activity of key enzymes in glutamine metabolism were evaluated by WB and enzyme activity assays, respectively. Furthermore, intervention experiments utilizing the glutamine metabolism inhibitor BPTES were conducted to validate the function of glutamine metabolism in Mtb-induced M2 polarization.

RESULTS: In vivo assay revealed that Mtb infection markedly promoted M2 polarization of macrophages in murine lung tissues. Flow cytometry detected an increased proportion of CD206 + macrophages, and immunohistochemical staining further confirmed elevated expression of the M2 markers Arg1 and Ym-1. In vitro experiments further confirmed that Mtb infection induced macrophage transition to the M2 phenotype and activated the glutamine metabolism pathway. Critically, the glutamine metabolism inhibitor BPTES substantially reversed Mtb-induced M2 polarization of macrophages, as evidenced by suppressed levels of M2 markers' expression and STAT6 phosphorylation. These results confirmed that glutamine metabolism was a key driver of Mtb-induced M2 macrophage polarization.

CONCLUSION: This study demonstrates that Mtb drives the polarization of host macrophages toward an M2 phenotype favorable for pathogen survival by activating the host glutamine metabolic pathway, revealing a novel mechanism by which pathogens exploit host metabolism to achieve immune evasion.