Rationale: Sepsis is serious disease which is a leading cause of death in non-coronary intensive care units worldwide. Innate immunity is a protective mechanism against sepsis. Although NLRC4 inflammasome has been shown to be a critical component of host defense against systemic pathogens, its role in modulating both innate and adaptive immune responses in sepsis remains elusive.

Methods: We used NLRC4 gene-deficient and wild-type (WT) mice to study sepsis by cecal ligation and puncture (CLP). Survival, bacterial burden in the lung and extra-pulmonary organs, and leukocyte influx to the peritoneal lavage fluid (PF) were analyzed. Chemokines and cytokines in PF were quantified using ELISA. Mice were also subjected to CLP-induced sepsis with or without chlorinate-mediated macrophage depletion. Flow cytometric analysis was performed to compare the T-cell population. Mice were co-housed to compare the gut microbiota's effect on bacterial-burden.

Results: NLRC4 deficiency improves survival and bacterial clearance in mice with CLP-induced sepsis. We found higher recruitment of macrophages but lower levels of cytokines and chemokines in PF following sepsis in NLRC4 gene-deficient mice. Co-housing of WT and KO mice suggests that NLRC4 regulates host defense in CLP-induced sepsis independently of gut microbiota. Moreover, macrophage depletion experiments demonstrate that NLRC4 deficiency protects macrophages from sepsis-induced immune dysfunction. Flow cytometric analysis revealed higher CD4+, CD8+, INF-γ+CD8+ T cells, and NK cells in the spleen of NLRC4-deficient mice following sepsis.

Conclusion:  NLRC4 activation has a detrimental role in sepsis through hyper-inflammation and T cell exhaustion. Therefore, inhibition of NLRC4 inflammasome can be therapeutically beneficial in septic patients.

Key Words: NLRC4, Sepsis, hyper-inflammation