NK cell-derived exosomes restrict Mycobacterium tuberculosis infection by inhibiting cellular ferroptosis

Tuberculosis (TB) continues to pose a formidable global health threat, prompting the exploration of novel treatment strategies. The role of trace elements, especially iron, in TB pathogenesis is becoming increasingly recognized. Ferroptosis, an iron-dependent cell death process, has emerged as a key antimicrobial mechanism. This study aims to investigate whether exosomes derived from natural killer cells (NK-exo) can enhance host immune resistance to Mycobacterium tuberculosis (MTB) through the regulation of ferroptosis.

We evaluated the therapeutic potential of NK-exo in both MTB-infected Ana-1 macrophages and a mouse model. Western blotting and RT-qPCR were employed to detect changes in the expression of ferroptosis proteins. Histopathological damage was assessed via H&E staining, and bacterial loads were quantified by CFU assays. To establish ferroptosis suppression as the mechanism through which NK-exo mitigates MTB infection, we treated cells with the ferroptosis activator RSL3 and examine whether this intervention consequently reversed the protective effects of NK-exo.

In both infected macrophages and mouse lung tissues, NK-exo treatment reduced the MTB load and effectively suppressed ROS accumulation and ferroptosis. Mechanistically, NK-exo exhibited dual regulation of the ferroptosis pathway by upregulating the expression of GPX4 while concomitantly downregulating the expression of SLC7A11, ACSL4, and TFRC. Crucially, the protective effects of NK-exo were abolished by co-treatment with RSL3, confirming that its mechanism hinges on the regulation of the ferroptosis pathway.

NK-exo mitigates MTB infection-induced lipid peroxidation and histopathological damage by targeting pivotal regulators of ferroptosis. These findings highlight the promise of NK-exo as a novel, cell-free immunotherapeutic strategy for Tuberculosis.