Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 12, Pages 3531-3541Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171048
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Funding
- ERC under European Union's Horizon research and innovation programme [648768]
- ANR [ANR-14-CE14-0009-01]
- Fondation ARC [PGA120140200817]
- Italian Foundation for Cancer Research (AIRC)
- Institut National de la Sante et de la Recherche Medicale, Centre National de la Recherche Scientifique, Aix-Marseille University
- Marseille-Immunopole
- European Research Council (ERC) [648768] Funding Source: European Research Council (ERC)
- Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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Upon infection, the immune system produces inflammatory mediators important for pathogen clearance. However, inflammation can also have deleterious effect on the host and is tightly regulated. Immune system-derived cytokines stimulate the hypothalamic-pituitary-adrenal (HPA) axis, triggering endogenous glucocorticoid production. Through interaction with ubiquitously expressed glucocorticoid receptors (GRs), this steroid hormone has pleiotropic effects on many cell types. Using a genetic mouse model in which the gene encoding the GR is selectively deleted in NKp46(+) innate lymphoid cells (ILCs), we demonstrated a major role for the HPA pathway in host resistance to endotoxin-induced septic shock. GR expression in group 1 ILCs is required to limit their IFN-gamma production, thereby allowing the development of IL-10-dependent tolerance to endotoxin. These findings suggest that neuroendocrine axes are crucial for tolerization of the innate immune system to microbial endotoxin exposure through direct corticosterone-mediated effects on NKp46-expressing innate cells, revealing a novel strategy of host protection from immunopathology.
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