VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation

Area of Science:

• Immunology
• Cell Biology
• Mitochondrial Biology

Background:

• Sepsis involves immune dysregulation and high mortality.
• Splenic T cells play a role in systemic inflammation, but mechanisms are unclear.
• Bacterial endotoxin lipopolysaccharide (LPS) is a key sepsis trigger.

Purpose of the Study:

• Investigate LPS impact on mouse spleen tissue and T cells.
• Elucidate the role of mitochondrial dysfunction and DNA release in T cell inflammation.
• Identify novel therapeutic targets for sepsis.

Main Methods:

• LPS challenge in mouse spleen tissue and primary T cells.
• Measurement of inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-18).
• Transcriptomic profiling, mitochondrial ROS, Ca2+ mobilization, and mtDNA release assays.
• VDAC1 oligomerization assessment and inhibition using VBIT-12.
• Analysis of the cGAS-STING-TBK1 signaling pathway.

Main Results:

• LPS induced splenic inflammation and elevated cytokine levels.
• LPS triggered mitochondrial dysfunction, including mtROS production, Ca2+ flux, and mtDNA release in T cells.
• VDAC1 oligomerization was critical for LPS-induced mtDNA release and cGAS-STING-TBK1 activation.
• Inhibition of VDAC1 oligomerization with VBIT-12 suppressed inflammation.

Conclusions:

• A novel pathway links LPS-induced VDAC1 oligomerization to mtDNA release and cGAS-STING-TBK1 activation in T cells.
• This mechanism contributes to T cell-mediated immunopathology in endotoxemia.
• VDAC1 and mitochondrial function represent potential therapeutic targets for sepsis.