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Immunity. 2018 Jan 16;48(1):120-132.e8. doi: 10.1016/j.immuni.2017.11.020.

Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.

Author information

1
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden.
2
Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal.
3
Immunology & Allergy Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
4
Unité Stroma, Inflammation & Tissue Repair, Institut Pasteur, 75724 Paris, France; INSERM U1224, 75724 Paris, France.
5
Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
6
Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9PL, UK.
7
I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
8
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
9
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute. Electronic address: richard.flavell@yale.edu.
10
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: tim.willinger@ki.se.

Abstract

Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis.

KEYWORDS:

EBI2; GPR183; cell migration; colon; inflammation; innate lymphoid cells; lymphoid tissue; oxysterols

PMID:
29343433
PMCID:
PMC5772175
DOI:
10.1016/j.immuni.2017.11.020
[Indexed for MEDLINE]
Free PMC Article

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