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PMID: 24927559 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 111 ·No. 25 ·2014-06-24 ·Pages E2559-66

Ermann J, Staton T, Glickman JN, de Waal Malefyt R, Glimcher LH

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.

MeSH Terms
Animals Bacteria/immunology Bone Marrow Cells/cytology,immunology Chemokines/genetics,immunology Colitis, Ulcerative/genetics,immunology DNA-Binding Proteins/genetics,immunology Dendritic Cells/immunology,pathology Humans Interleukin-17/genetics,immunology Interleukin-23/genetics,immunology Intestines/immunology,microbiology,pathology Mice Mice, Knockout Receptor-Interacting Protein Serine-Threonine Kinase 2 Receptor-Interacting Protein Serine-Threonine Kinases/genetics,immunology Signal Transduction/genetics,immunology T-Box Domain Proteins/genetics,immunology
Chemicals
Chemokines DNA-Binding Proteins Il17a protein, mouse Interleukin-17 Interleukin-23 Rag2 protein, mouse T-Box Domain Proteins T-box transcription factor TBX21 Receptor-Interacting Protein Serine-Threonine Kinase 2 Receptor-Interacting Protein Serine-Threonine Kinases Ripk2 protein, mouse
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ermann Joerg
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115;Harvard Medical School, Boston, MA 02115;
Staton Tracy
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115;
Glickman Jonathan N
Department of Pathology, Harvard Medical School, Boston, MA 02115;Miraca Life Sciences, Newton, MA 02464;
de Waal Malefyt Rene
Biologics Discovery, Merck Research Laboratories, Palo Alto, CA 94304; and.
Glimcher Laurie H
Weill Cornell Medical College, New York, NY 10065 lglimche@med.cornell.edu.
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1408540111
Email
lglimche@med.cornell.edu
Published
2014-06-24
Epub
2014-00-09
Pages
E2559-66
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4078823
Subset
IM
Grants
NIDDK NIH HHS · P30 DK034854 · United States
NCI NIH HHS · R01 CA112663 · United States
NIDDK NIH HHS · 5-P30 DK034854 · United States
NCI NIH HHS · CA112663 · United States
External Links
PubMed source DOI: 10.1073/pnas.1408540111 PMC Full Text View journal details
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