NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex...

Area of Science:

• Immunology
• Cellular Metabolism
• Infectious Disease

Background:

• Sepsis leads to immunosuppression by impairing innate immune cell function and metabolism.
• Current therapies to address sepsis-induced immunosuppression are limited.
• NOD-like receptor family CARD domain containing-3 (NLRC3) is implicated in immune regulation.

Purpose of the Study:

• To investigate the role of NLRC3 in sepsis-induced immunosuppression.
• To elucidate the molecular mechanisms by which NLRC3 affects immune cell metabolism and function.
• To evaluate NLRC3 as a potential therapeutic target for sepsis.

Main Methods:

• Correlated high NLRC3 levels with monocyte/macrophage glycolytic defects in septic patients and mice.
• Utilized myeloid-specific NLRC3 deletion in mouse models of sepsis.
• Investigated the interaction of NLRC3 with NF-κB p65, NFAT5, TRAF6, mTOR, and p300.
• Administered intrapulmonary recombinant adeno-associated virus with a macrophage-specific NLRC3 deletion vector.

Main Results:

• High NLRC3 levels were associated with impaired macrophage glycolysis and immunosuppression in sepsis.
• Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis outcomes.
• NLRC3 was found to inhibit NF-κB p65 binding to NFAT5 by sequestering mTOR and p300.
• Genetic inhibition of NLRC3 enhanced NF-κB binding to the NFAT5 promoter.
• Intrapulmonary delivery of NLRC3 deletion vector improved defense in septic mice.

Conclusions:

• NLRC3 plays a critical role in mediating innate immune dysfunction and immunosuppression during sepsis.
• Targeting NLRC3, particularly its interaction with mTOR and p300, offers a promising therapeutic strategy for sepsis.
• Restoring macrophage glycolysis through NLRC3 inhibition can enhance host defense against sepsis.