Regulation of dendritic cell function improves survival in experimental sepsis through immune chaperone

Abstract

Dendritic cells (DCs) are professional Ag-presenting cells that play a critical role in both innate and adaptive immune responses. DCs recognize and respond to bacteria through multiple PRRs, including TLRs. Heat shock protein gp96/grp94 is a master essential chaperone for TLRs in the endoplasmic reticulum. We generated DC-specific gp96-knockout (KO) mice and showed that gp96 KO DCs were unable to respond to multiple TLR ligands. TLR-mediated hyperinflammatory response can lead to sepsis. However, the roles of neither DCs nor the DC-intrinsic gp96 in the process are completely understood. In a LPS-induced sepsis model, we hereby found that deletion of gp96 in DCs significantly reduced serum TNF-α levels and improved survival. Furthermore, using the well-defined polymicrobial sepsis model of cecal ligation and puncture, we found that DC-specific ablation of gp96 improved survival with significantly attenuated liver and renal injuries, decreased circulating inflammatory cytokines, altered DC maturation and activation, and increased serum Ig. Collectively, we demonstrate that deletion of gp96 in DCs is beneficial in protecting mice against sepsis induced by both endotoxemia and polymicrobial infections. We conclude that targeting gp96 in DCs may provide a potential novel approach for reducing the morbidity and mortality of sepsis.

The development of endoplasmic reticulum-related gene signatures and the immune infiltration analysis of sepsis

“…Based on the expression profile of the four ERRGs, we divided the patients with sepsis into two molecular subgroups. After the analysis of immune infiltration characteristics in the two molecular subgroups, the immune-related function was proven to play an essential role in the development of sepsis, which is in concordance with previous literature ( 32 , 33 ). Notably, a remarkable difference was found in 23 kinds of immune cells between the two sepsis subgroups, especially activated B cells, CD4+ T cells, immature dendritic cells, and plasmacytoid dendritic cells.…”

Protective Role of Genetic Variants in HSP90 Genes-Complex in COPD Secondary to Biomass-Burning Smoke Exposure and Non-Severe COPD Forms in Tobacco Smoking Subjects

“…Deletion of GRP94/GP96 in different cells induce a hipoinflammatory and autoimmune state via instability in TLR and other molecules; in macrophages generate TLR null cells [45], in dendritic cell reduces the immune response to sepsis [52], while in Treg-cells, the levels of FOXP3 are reduced, inducing IFN-γ and IL-17 overproduction [53].…”

Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

“…Previous studies of sepsis in animal models and in human patients have shown that the number of DCs was depleted in both lymph and non-lymphoid organs [11]. Using the cecal ligation and puncture (CLP) mouse model of sepsis, the number of CD11c+ DC was found to be lower in the spleen and lymph nodes than that in sham operation groups [12]. In peripheral organs of septic patients, clinical trials have shown that the number of interstitial DCs was remarkably lower than that in non-septic patients [13].…”