Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis
Berna Kaya,
Cristian Doñas,
Philipp Wuggenig,
Oscar E. Diaz,
Rodrigo A. Morales,
Hassan Melhem,
Pedro P. Hernández,
Tanay Kaymak,
Srustidhar Das,
Petr Hruz,
Yannick Franc,
Florian Geier,
C. Korcan Ayata,
Eduardo J. Villablanca,
Jan Hendrik Niess
Affiliations
Berna Kaya
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Cristian Doñas
Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center for Molecular Medicine (CMM), 17176 Stockholm, Sweden
Philipp Wuggenig
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Oscar E. Diaz
Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center for Molecular Medicine (CMM), 17176 Stockholm, Sweden
Rodrigo A. Morales
Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center for Molecular Medicine (CMM), 17176 Stockholm, Sweden
Hassan Melhem
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Pedro P. Hernández
Institut Curie, PSL Research University, INSERM U934/CNRS UMR3215, Development and Homeostasis of Mucosal Tissues Group, 75005 Paris, France
Tanay Kaymak
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Srustidhar Das
Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center for Molecular Medicine (CMM), 17176 Stockholm, Sweden
Petr Hruz
University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital of Basel, 4031 Basel, Switzerland
Yannick Franc
Center for Primary Care and Public Health (Unisanté), University of Lausanne, 1011 Lausanne, Switzerland
Florian Geier
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; Swiss Institute of Bioinformatics, 4031 Basel, Switzerland
C. Korcan Ayata
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
Eduardo J. Villablanca
Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden; Center for Molecular Medicine (CMM), 17176 Stockholm, Sweden; Corresponding author
Jan Hendrik Niess
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland; University Center for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital of Basel, 4031 Basel, Switzerland; Corresponding author
Summary: Single-nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, the mechanisms by which GPR35 modulates intestinal immune homeostasis remain undefined. Here, integrating zebrafish and mouse experimental models, we demonstrate that intestinal Gpr35 expression is microbiota dependent and enhanced upon inflammation. Moreover, murine GPR35+ colonic macrophages are characterized by enhanced production of pro-inflammatory cytokines. We identify lysophosphatidic acid (LPA) as a potential endogenous ligand produced during intestinal inflammation, acting through GPR35 to induce tumor necrosis factor (Tnf) expression in macrophages. Mice lacking Gpr35 in CX3CR1+ macrophages aggravate colitis when exposed to dextran sodium sulfate, which is associated with decreased transcript levels of the corticosterone-generating gene Cyp11b1 and macrophage-derived Tnf. Administration of TNF in these mice restores Cyp11b1 expression and intestinal corticosterone production and ameliorates DSS-induced colitis. Our findings indicate that LPA signals through GPR35 in CX3CR1+ macrophages to maintain TNF-mediated intestinal homeostasis.
