NLRC4 deficiency improves host protection during sepsis by regulating macrophage and T-cell responses

Sepsis followed by multiple organ failure is a leading cause of death in noncoronary intensive care units. While the NLRC4 inflammasome has been shown to play a crucial role in the innate immune response, the role of NLRC4 in sepsis remains unclear. Here, we used NLRC4 gene-deficient mice to explore its role in cecal ligation and puncture (CLP)-induced polymicrobial sepsis. Survival, bacterial clearance in the lung and extrapulmonary organs, and leukocyte influx to the peritoneum were determined. Chemokines and cytokines in the peritoneal fluid (PF) were quantified using ELISA. Mice were co-housed to compare the gut microbiota's effect on bacterial burden following sepsis. Here, we report that NLRC4 deficiency improves host survival and bacterial clearance in mice with CLP-induced sepsis. Nlrc4-/- mice displayed reduced numbers of total leukocytes in the PF, including neutrophils compared to wild-type (WT) mice at 12 and 24 h post-CLP, although the recruitment of macrophages in NLRC4 knockout mice was higher at 12 h. Nlrc4-/- mice displayed lower levels of cytokines and chemokines in PF following sepsis. Co-housing of WT and Nlrc4-/- mice suggests that NLRC4 regulates host defense in CLP-induced sepsis independently of gut microbiota. Depletion of macrophages demonstrated that NLRC4 deficiency protects macrophages from sepsis-induced immune dysfunction. Moreover, we observed higher CD4+, CD8+, IFN-γ+CD8+, and NK cell subsets in the spleen and lower level of apoptosis of spleen cells of NLRC4-deficient mice after sepsis. Overall, these findings identify that NLRC4 activation has a detrimental role in sepsis through modulating macrophages and T-cell responses.