Dendritic cell-intrinsic TLR signaling regulates polymicrobial sepsis

Abstract

Abstract Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in both innate and adaptive immune response. DCs recognize and respond to bacteria through multiple pattern-recognition receptors, including Toll-like receptors (TLRs). Heat shock protein gp96 is a master chaperone for TLRs in the endoplasmic reticulum and plays critical roles in innate immunity. Sepsis is a clinical syndrome caused by a severe immune response to infection. However, the role of DC-intrinsic TLRs in sepsis has not been studied. Using a unique DC-specific gp96 knockout (KO) mouse model, we observed that gp96-deficient DCs were unable to respond to both surface and intracellular TLR ligands. Our DC-specific gp96 deficient mice present a DC-specific pan TLR KO mouse model. We challenged WT and KO mice with a lethal dose of LPS, and we found that WT mice significantly produced more serum TNF-a than did KO mice. Consistent with the detrimental effect of this cytokine in sepsis, we found that the WT mice were more susceptible to LPS-induced sepsis than the KO mice. Furthermore, using a well-defined sepsis model of cecal ligation and puncture (CLP), we found that KO mice exhibited significant higher survival rates (33%) compared to littermate WT controls (5%, p<0.05). Collectively, our study demonstrates that DC-specific gp96 KO mice were able to mount effective responses against polymicrobial sepsis, underscoring the importance of DC-intrinsic TLR signaling in innate immunity and sepsis outcomes.