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

Johanna Emgård (1) , Hana Kammoun (1) , Bethania García-Cassani (2) , Julie Chesné (2) , Sara Parigi (1) , Jean-Marie Jacob (3) , Hung-Wei Cheng (4) , Elza Evren (1) , Srustidhar Das (1) , Paulo Czarnewski (1) , Natalie Sleiers (1) , Felipe Melo-Gonzalez (5) , Egle Kvedaraite (1) , Mattias Svensson (1) , Elke Scandella (4) , Matthew Hepworth (5) , Samuel Huber (6) , Burkhard Ludewig (4) , Lucie Peduto (3) , Eduardo Villablanca (1) , Henrique Veiga-Fernandes (2) , Joao Pereira (7) , Richard A. Flavell (7, 8) , Tim Willinger (1, 7)

1 Karolinska Institutet [Stockholm]
2 Champalimaud Centre for the Unknown [Lisbon]
3 Stroma, inflammation et réparation tissulaire - Stroma, Inflammation and Tissue Repair
4 Brustzentrum Kantonsspital St. Gallen
5 University of Manchester [Manchester]
6 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
7 YSM - Yale School of Medicine [New Haven, Connecticut]
8 HHMI - Howard Hughes Medical Institute

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

Domains: Immunology

Johanna Emgård, Hana Kammoun, Bethania García-Cassani, Julie Chesné, Sara Parigi, et al.. Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation. Immunity, 2018, 48 (1), pp.120 - 132.e8. ⟨10.1016/j.immuni.2017.11.020⟩. ⟨pasteur-01716331⟩