title: Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet-/-.Rag2-/- (TRUC) mice.
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.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115;Harvard Medical School, Boston, MA 02115;
authors.forename: Joerg
authors.initials: J
authors.lastname: Ermann
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Tracy
authors.initials: T
authors.lastname: Staton
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115;Miraca Life Sciences, Newton, MA 02464;
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.affiliation: Biologics Discovery, Merck Research Laboratories, Palo Alto, CA 94304; and.
authors.forename: Rene
authors.initials: R
authors.lastname: de Waal Malefyt
authors.affiliation: Weill Cornell Medical College, New York, NY 10065 lglimche@med.cornell.edu.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology*; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D018925:Chemokines; D004268:DNA-Binding Proteins; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse