Suppression of Dendritic Cell-Derived IL-12 by Endogenous Glucocorticoids Is Protective in LPS-Induced Sepsis

Abstract

Sepsis, an exaggerated systemic inflammatory response, remains a major medical challenge. Both hyperinflammation and immunosuppression are implicated as causes of morbidity and mortality. Dendritic cell (DC) loss has been observed in septic patients and in experimental sepsis models, but the role of DCs in sepsis, and the mechanisms and significance of DC loss, are poorly understood. Here, we report that mice with selective deletion of the glucocorticoid receptor (GR) in DCs (GRCD11c-cre) were highly susceptible to LPS-induced septic shock, evidenced by elevated inflammatory cytokine production, hypothermia, and mortality. Neutralizing anti-IL-12 antibodies prevented hypothermia and death, demonstrating that endogenous GC-mediated suppression of IL-12 is protective. In LPS-challenged GRCD11c-cre mice, CD8+ DCs were identified as the major source of prolonged IL-12 production, which correlated with elevations of NK cell-derived IFN-γ. In addition, the loss of GR in CD11c+ cells rescued LPS-induced loss of CD8+ DCs but not other DC subsets. Unlike wild-type animals, exposure of GRCD11c-cre mice to low-dose LPS did not induce CD8+ DC loss or tolerance to subsequent challenge with high dose, but neutralization of IL-12 restored the ability of low-dose LPS to tolerize. Therefore, endogenous glucocorticoids blunt LPS-induced inflammation and promote tolerance by suppressing DC IL-12 production.

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

“…Moreover, the physiological effects of glucocorticoids on dendritic cells, regulatory T cells, or Th17 cells in the endometrium have not been studied. Dendritic cell-specific NR3C1 knockout mice have been utilized in models of sepsis and arthritis but have not been evaluated for functions relating to fertility [95, 96]. T cell-specific ablation of NR3C1 has been reported, although Cre recombinase activity occurs early in T-cell development and prevents discriminating the contribution of glucocorticoid signaling among T cell subtypes [91].…”

The Role of Dendritic and Endothelial Cells in Cardiorenal Syndrome

“…These changes in DC markers are likely to represent an altered function of DCs in the setting of inflammatory conditions [64]. In a mice model, the loss of immature DCs and the inability of mature splenic DCs to produce Th1 cytokines (i.e., IL-12) result in an immunosuppressive effect [65]. Additionally, in LPS-induced sepsis, endogenous glucocorticoids (immunosuppressive hormones) protect mice from LPS-induced septic shock by suppressing DC production of IL-12 (a cytokine required for IFN-γ production and lethality in LPS-induced septic shock) [65].…”

“…In a mice model, the loss of immature DCs and the inability of mature splenic DCs to produce Th1 cytokines (i.e., IL-12) result in an immunosuppressive effect [65]. Additionally, in LPS-induced sepsis, endogenous glucocorticoids (immunosuppressive hormones) protect mice from LPS-induced septic shock by suppressing DC production of IL-12 (a cytokine required for IFN-γ production and lethality in LPS-induced septic shock) [65]. Kobayashi et al[66] reported that B and T lymphocyte attenuator (CD272) inhibits LPS-induced endotoxic shock by suppressing TLR4 signaling and proinflammatory cytokine production in DCs.…”

“…There is growing evidence to suggest that the phenotypes and functions of DCs in animals and humans are similar in some aspects. For example, loss of DCs has been observed in septic patients and in experimental sepsis models [65]. The B and T lymphocyte attenuator directly inhibits LPS response in DCs; thus, agonistic agents for the B and T lymphocyte attenuator might have therapeutic potential for LPS-induced endotoxic shock [66].…”

Effects of Corticosterone on Immune Functions of Cultured Rat Splenic Lymphocytes Exposed to Aluminum Trichloride

“…Pharmacological concentration of GCs can inhibit lymphocyte proliferation, differentiation and maturation, and synthesis, release and efficacy of cytokines in vivo and in vitro [12][13][14][15][16]. Physiological concentration of GCs enhances immunoglobulin production of human lymphocytes in vitro [17].…”