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

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 1; pp. 120 - 132.e8
• Main Authors: Emgård, Johanna, Kammoun, Hana, García-Cassani, Bethania, Chesné, Julie, Parigi, Sara M., Jacob, Jean-Marie, Cheng, Hung-Wei, Evren, Elza, Das, Srustidhar, Czarnewski, Paulo, Sleiers, Natalie, Melo-Gonzalez, Felipe, Kvedaraite, Egle, Svensson, Mattias, Scandella, Elke, Hepworth, Matthew R., Huber, Samuel, Ludewig, Burkhard, Peduto, Lucie, Villablanca, Eduardo J., Veiga-Fernandes, Henrique, Pereira, João P., Flavell, Richard A., Willinger, Tim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.01.2018; Elsevier Limited; Elsevier; Cell Press
• Subjects: Animal tissues; Animals; cell migration; Cell Movement - genetics; Chemokines; Cholesterol; Colitis; Colitis - immunology; Colitis - metabolism; Colitis - pathology; Colon; Colon - immunology; Colon - pathology; Cytokines; Cytokines - metabolism; Dendritic cells; EBI2; Enzymes; Flow Cytometry; Fluorescent Antibody Technique; Follicles; G protein-coupled receptors; GPR183; Homeostasis; Immunology; Inflammation; Inflammatory bowel disease; innate lymphoid cells; Life Sciences; Ligands; Lymphocytes - metabolism; Lymphocytes - pathology; Lymphoid cells; Lymphoid tissue; Lymphoid Tissue - metabolism; Lymphoid Tissue - pathology; Medicin och hälsovetenskap; Metabolites; Mice; Neurons; oxysterols; Oxysterols - metabolism; Phenotypes; Real-Time Polymerase Chain Reaction; Receptor mechanisms; Receptors; Receptors, G-Protein-Coupled - metabolism; Rodents; Signal Transduction; Small intestine; Stromal cells; Transcription factors; United States > US; oxysterols; lymphoid tissue; inflammation; GPR183; EBI2; cell migration; colon; innate lymphoid cells
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2017.11.020

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. [Display omitted] •ILC3s sense cholesterol metabolites (oxysterols) through the receptor GPR183•GPR183 and its ligand 7α,25-OHC promote ILC3 migration to CPs and ILFs•GPR183 and 7α,25-OHC are critical for CP and ILF formation in the colon•GPR183 controls inflammatory tissue remodeling during immune-mediated colitis ILC3s maintain healthy organ function in the intestine, but how ILC3s directly detect environmental cues is poorly understood. Emgård et al. find that GPR183 and oxysterols control the localization and LTi function of ILC3s and thereby promote the formation of colonic lymphoid tissues in the steady state and inflammation.