Necroptotic signaling is primed in Mycobacterium tuberculosis-infected macrophages, but its pathophysiological...

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• Mixed lineage kinase domain-like (MLKL)-dependent necroptosis is hypothesized to promote Mycobacterium tuberculosis (Mtb) dissemination by causing infected macrophage death.
• Inhibiting necroptosis is a potential therapeutic strategy for Mtb infection.

Purpose of the Study:

• To definitively establish the pathophysiological role of necroptosis in Mtb infection using human and murine models.
• To investigate the mechanisms by which Mtb infection influences the necroptotic pathway.

Main Methods:

• Utilized human pharmacologic and murine genetic models to study Mtb infection.
• Assessed macrophage survival, lung histopathology, and bacterial burdens in MLKL-deficient or RIPK1 inhibitor-treated models.
• Analyzed intracellular signaling pathways, including MLKL, TNFR1, ZBP1, and cIAP1, in Mtb-infected macrophages.

Main Results:

• Mtb infection upregulated pro-necroptotic signaling molecules (MLKL, TNFR1, ZBP1) and downregulated cIAP1, creating a pro-necroptotic environment.
• Blocking necroptosis via Mlkl deletion or RIPK1 inhibition did not affect Mtb-infected macrophage survival in vitro.
• MLKL-deficiency or RIPK1 inhibition in vivo did not alter disease outcomes, lung pathology, or bacterial burden in mice.
• cFLIP upregulation was identified as a potential mechanism restricting Mtb-induced necroptosis.

Conclusions:

• Macrophage necroptosis is not essential for Mtb control and is actively restricted by the host during infection.
• Mechanisms like cFLIP upregulation may abrogate Mtb's ability to exploit necroptosis.
• Variability in these host restriction mechanisms could contribute to Mtb disease heterogeneity.