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

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...

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Published inPLoS biology Vol. 13; no. 10; p. e1002269
Main Authors Li, Caiyi C, Munitic, Ivana, Mittelstadt, Paul R, Castro, Ehydel, Ashwell, Jonathan D
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.10.2015
Public Library of Science (PLoS)
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Summary: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 (GR(CD11c-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 GR(CD11c-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 GR(CD11c-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.
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Conceived and designed the experiments: CCL IM PRM JDA. Performed the experiments: CCL IM PRM EC. Analyzed the data: CCL IM PRM JDA. Wrote the paper: CCL IM JDA.
The authors have declared that no competing interests exist.
Current address: Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.1002269