NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-KB-NFAT5 complex during septic immunosuppression

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-KB p65 binding to nuclear factor of acti-vated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immuno-suppressive macrophages. This is achieved by decreasing NF-KB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic in-hibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-KB binding to the NFAT5 promoter in con-cert with p300. Furthermore, intrapulmonary delivery of re-combinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.

Automated summary

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis. This study found that high levels of NLRC3 are correlated with glycolytic defects and immunosuppression in septic patients and mice. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits NF-KB p65 binding to NFAT5, thereby controlling the expression of glycolytic genes and proinflammatory cytokines. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-KB binding to NFAT5 promoter. Intrapulmonary delivery of a recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector improved the defense of septic mice. These findings suggest that NLRC3 mediates critical aspects of innate immunity and could be a potential therapeutic target for sepsis-induced immunosuppression.