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Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):E2559-66. doi: 10.1073/pnas.1408540111. Epub 2014 Jun 9.

Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet-/-.Rag2-/- (TRUC) mice.

Author information

1
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115;Harvard Medical School, Boston, MA 02115;
2
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;
3
Department of Pathology, Harvard Medical School, Boston, MA 02115;Miraca Life Sciences, Newton, MA 02464;
4
Biologics Discovery, Merck Research Laboratories, Palo Alto, CA 94304; and.
5
Weill Cornell Medical College, New York, NY 10065 lglimche@med.cornell.edu.

Abstract

T-bet(-/-).Rag2(-/-) (TRUC) mice spontaneously develop microbiota-driven, TNF-mediated large bowel inflammation that resembles human ulcerative colitis. We show here that IL-23 and IL-1-dependent secretion of IL-17A by innate lymphoid cells (ILCs; defined as CD45(+)lin(-)Thy1(hi)NKp46(-)) is a second critical pathway in this model. Using an in vitro coculture system of bone marrow-derived dendritic cells (DCs) and freshly isolated FACS-purified ILCs, we demonstrate that IL-23 and IL-1 secreted by DCs in response to microbial stimulation work together to induce IL-17A production by ILCs. TNF is not required for IL-17A secretion by ILCs in vitro but synergizes with IL-17A to induce the expression of neutrophil-attracting chemokines. Upstream, activation of the IL-23/IL-17A axis is regulated by nucleotide-binding oligomerization domain containing (Nod)/receptor-interacting serine-threonine kinase 2 (Ripk2) signals in DCs. Genetic ablation of the Nod/Ripk2 signaling pathway protects TRUC mice from developing colitis without affecting the colitogenicity of the intestinal microbiota. Our data provide insight into the complex network of interactions between IL-17A-secreting ILCs and other components of the innate immune system in the development of colitis.

PMID:
24927559
PMCID:
PMC4078823
DOI:
10.1073/pnas.1408540111
[Indexed for MEDLINE]
Free PMC Article

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