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 in | PLoS biology Vol. 13; no. 10; p. e1002269 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
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01.10.2015
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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 (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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AbstractList | 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.sup.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.sup.CD11c-cre] mice, [CD8.sup.+] 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.sup.+] DCs but not other DC subsets. Unlike wildtype animals, exposure of [GR.sup.CD11c-cre] mice to low-dose LPS did not induce [CD8.sup.+] 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. 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-[gamma]. 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. 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. Lipopolysaccharide (LPS) from bacteria causes the increased production of endogenous glucocorticoids, protecting mice from sepsis and contributing to LPS tolerance by suppressing production of interleukin-12 (IL-12) by dendritic cells and causing the death of the primary producers of IL-12. Read the Synopsis. Sepsis refers to life-threatening systemic inflammation, often caused by infection with bacteria that produce lipopolysaccharide (LPS). Glucocorticoids, immunosuppressive hormones produced by the adrenals, have been used to treat sepsis for over 50 y, but little is known about the role of endogenous (naturally occurring) glucocorticoids in systemic inflammation. Macrophages have been considered the primary source of inflammatory mediators (cytokines) and a target for glucocorticoid-mediated suppression. The possible role of another immune cell population, dendritic cells, has not been explored in detail. We created a mouse model in which the glucocorticoid receptor is selectively deleted in dendritic cells (DCs). We found that the elevation of glucocorticoids that accompanies sepsis protects mice from LPS-induced septic shock by suppressing DC production of IL-12, a cytokine that causes the secretion of other inflammatory mediators. In addition, LPS-induced glucocorticoids caused the death of a subset of DCs that are the primary producers of IL-12. Glucocorticoids were also found to be important for the phenomenon of "LPS tolerance", in which inoculation with low-dose LPS makes mice resistant to rechallenge with a high dose. This unexpected role of DC-produced IL-12 and its suppression by endogenous glucocorticoids may account, at least in part, for the known association of adrenal insufficiency and prolonged 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 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. |
Audience | Academic |
Author | Munitic, Ivana Li, Caiyi C Mittelstadt, Paul R Ashwell, Jonathan D Castro, Ehydel |
AuthorAffiliation | Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America National Jewish Medical and Research Center/Howard Hughes Medical Institute, UNITED STATES |
AuthorAffiliation_xml | – name: National Jewish Medical and Research Center/Howard Hughes Medical Institute, UNITED STATES – name: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America |
Author_xml | – sequence: 1 givenname: Caiyi C surname: Li fullname: Li, Caiyi C organization: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America – sequence: 2 givenname: Ivana surname: Munitic fullname: Munitic, Ivana organization: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America – sequence: 3 givenname: Paul R surname: Mittelstadt fullname: Mittelstadt, Paul R organization: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America – sequence: 4 givenname: Ehydel surname: Castro fullname: Castro, Ehydel organization: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America – sequence: 5 givenname: Jonathan D surname: Ashwell fullname: Ashwell, Jonathan D organization: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26440998$$D View this record in MEDLINE/PubMed |
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ContentType | Journal Article |
Copyright | COPYRIGHT 2015 Public Library of Science 2015 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Li CC, Munitic I, Mittelstadt PR, Castro E, Ashwell JD (2015) Suppression of Dendritic Cell-Derived IL-12 by Endogenous Glucocorticoids Is Protective in LPS-Induced Sepsis. PLoS Biol 13(10): e1002269. doi:10.1371/journal.pbio.1002269 |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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 |
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Snippet | Sepsis, an exaggerated systemic inflammatory response, remains a major medical challenge. Both hyperinflammation and immunosuppression are implicated as causes... Sepsis, an exaggerated systemic inflammatory response, remains a major medical challenge. Both hyperinflammation and immunosuppression are implicated as... |
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SubjectTerms | Animals Anti-Inflammatory Agents, Non-Steroidal - administration & dosage Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Antibodies, Neutralizing - administration & dosage Antibodies, Neutralizing - therapeutic use Care and treatment CD11c Antigen - genetics CD11c Antigen - metabolism Cells, Cultured Corticosteroids Crosses, Genetic Cytokines Dendritic cells Dendritic Cells - drug effects Dendritic Cells - immunology Dendritic Cells - metabolism Dendritic Cells - pathology Dose-Response Relationship, Drug Experiments Female Flow cytometry Glucocorticoids - agonists Glucocorticoids - antagonists & inhibitors Glucocorticoids - blood Glucocorticoids - metabolism Health aspects Immunity, Innate - drug effects Immunotherapy Inflammation Interleukin-12 - antagonists & inhibitors Interleukin-12 - blood Interleukin-12 - metabolism Lipopolysaccharides - toxicity Male Medical research Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mortality Receptors, Glucocorticoid - agonists Receptors, Glucocorticoid - antagonists & inhibitors Receptors, Glucocorticoid - genetics Receptors, Glucocorticoid - metabolism Risk factors Rodents Sepsis Septic shock Shock, Septic - immunology Shock, Septic - metabolism Shock, Septic - pathology Shock, Septic - prevention & control Signal Transduction - drug effects Software Specific Pathogen-Free Organisms Spleen - drug effects Spleen - immunology Spleen - metabolism Spleen - pathology Statistical analysis |
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Title | Suppression of Dendritic Cell-Derived IL-12 by Endogenous Glucocorticoids Is Protective in LPS-Induced Sepsis |
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