Irgm2 and Gate-16 cooperatively dampen Gram-negative bacteria-induced caspase-11 response

Area of Science:

• Immunology
• Cellular Biology
• Microbiology

Background:

• The non-canonical inflammasome, involving caspase-11 (rodents) or caspases-4/5 (humans), detects LPS in the cytosol.
• While crucial for bacterial defense, its overactivation leads to sepsis.

Purpose of the Study:

• To identify cellular components that regulate non-canonical inflammasome activation thresholds.
• To understand the mechanisms controlling inflammatory responses to Gram-negative bacteria.

Main Methods:

• Investigated the roles of IFN-inducible protein Irgm2 and ATG8 family member Gate-16.
• Utilized cultured macrophages and in vivo models.
• Assessed caspase-11 targeting, pyroptosis, and cytokine release.

Main Results:

• Irgm2 and Gate-16 cooperatively inhibit non-canonical inflammasome activation by Gram-negative bacteria.
• The Irgm2/Gate-16 axis reduces caspase-11 targeting to intracellular bacteria, lowering pyroptosis and cytokine release.
• Irgm2 or Gate-16 deficiency enhances caspase-11 targeting via GBP-dependent and independent pathways.

Conclusions:

• Irgm2 and Gate-16 act as key regulators of the non-canonical inflammasome.
• These findings elucidate mechanisms that fine-tune immune responses to bacterial infections and prevent sepsis.