NLRC4 deficiency enhances macrophage and T cell responses in polymicrobial sepsis

Abstract

Abstract Rationale Sepsis, a dysregulated systemic host inflammatory response to infection with organ failure, is leading cause of death in non-coronary intensive care unit worldwide. Recently, the NLRC4 inflammasome has been implicated in sensing pathogens and regulating inflammation during microbial infections. However, the role of NLRC4 in sepsis-induced immunosuppression, specifically macrophage dysfunction and T cell loss, is poorly understood. Methods We performed cecal ligation and puncture (CLP) to induce polymicrobial sepsis in wild type (C57BL6) and NLRC4-gene deficient (KO) mice. Cellular influx, bacterial burden, and host survival were measured. Macrophages were depleted using Clodronate liposomes. Depletion of lymphocytes, frequency of IFN-γ producing T cells, expression of costimulatory molecules in peritoneal macrophages were examined using flow cytometry. Results NLRC4 KO mice were protected from CLP-induced lethality. Furthermore, NLRC4 KO mice had reduced cellular influx, cytokine storm (IL-1b, TNF-a, MCP-1, CXCL-1, CXCL2), and bacterial burdens following CLP. NLRC4 KO mice were protected from sepsis-induced impairment of macrophage function and loss of CD4 and CD8 T cells. Peritoneal macrophages (CD11b+F4/80+) were protected from sepsis-induced loss of MHCII and CD86. Intriguingly, macrophage depletion prior to polymicrobial sepsis eliminated the NLRC4-mediated survival advantage. NLRC4 KO mice had increased frequency of IFN-γ producing T cells post-CLP. Conclusions These findings identify NLRC4 as a negative regulator of macrophage and T cell responses in sepsis and its selective inhibition as a potential therapeutic strategy to augment host immunity in sepsis.