Mycobacterium tuberculosis escapes immunity by regulating FUS/TLR4 and metabolic reprogramming to suppress macrophage activity

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, has been observed to manipulate macrophage polarization to survive. This investigation explored the mechanism by which Mtb modulates macrophage polarization through metabolic reprogramming, thereby enhancing its immune evasion capabilities. Utilizing Phorbol 12-myristate 13-acetate (PMA)-treated THP-1 monocytes (THP-1 macrophages) as the experimental model, we examined their vitality following Mtb infection. The M1 and M2 polarization markers of macrophages were assayed via flow cytometry and qRT-PCR. Simultaneously, glucose uptake, lactate production, ATP content, ECAR, and OCR of THP-1 macrophages were scrutinized. The interplay between FUS and TLR4 was evaluated through RNA immunoprecipitation and actinomycin D experiments. Post-overexpression of FUS or administration of TLR4 inhibitor TAK242 in THP-1 macrophages, the polarization markers, cytotoxicity, Mtb load, and glycolytic status were reassessed. Mtb can suppress the vitality of THP-1 macrophages, repress M1 phenotypic (CD86, IL-1β, and TNF-α), induce M2 phenotypic (CD206, IL-10, Arg-1), curtail glucose uptake, lactate production, and ATP levels, decrease ECAR, and augment OCR, concurrently diminishing TLR4 and FUS expression. Mtb appears capable of influencing the binding interaction between FUS and TLR4, with silencing of FUS reducing the stability of TLR4. Overexpression of FUS reverses the effects of Mtb on THP-1 macrophage polarization and glycolysis, simultaneously amplifying cytotoxic effect and decreasing Mtb load. However, the presence of TAK242 cannot eliminate the effects of FUS overexpression. Mtb orchestrates the regulation of the FUS/TLR4 axis to suppress macrophage glycolysis, thereby promoting polarization towards an M2 macrophage phenotype and ultimately facilitating immune evasion.