Kaya, Berna. Lysophosphatidic acid-mediated GPR35 signaling in CX3CR1+ macrophages regulates the intestinal cytokine milieu. 2020, Doctoral Thesis, University of Basel, Faculty of Science.
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Official URL: https://edoc.unibas.ch/78638/
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Abstract
Metabolites derived from the host or the microbiota regulate intestinal immunity via their G protein-coupled receptors (GPCRs). An aberrant relationship with the gut microbiota leads to gastrointestinal disorders, including inflammatory bowel diseases (IBD) in genetically predisposed individuals. G protein-coupled receptor (GPR)35 has been identified as one of the risk genes in IBD. Nonetheless, mechanisms by which GPR35 contributes to intestinal immunity are understudied. In this Ph.D. thesis, we aim to describe a role for macrophage-expressed GPR35 in regulating the inflammatory cues during intestinal inflammation. Using RNA sequencing, we found that GPR35 in colonic macrophages correlated with the expression of pro-inflammatory cytokines. Aiming to deorphanize the GPR35, we have used a GPCR ligand identification assay where LPA led to the activation of inhibitory G protein-mediated signaling in GPR35-transfected cells. In zebrafish and mice, we observed that LPA causes upregulation of pro-inflammatory cytokine genes in a GPR35-dependent manner. Specific deletion of GPR35 in CX3CR1+ macrophages resulted in exacerbated dextran sodium sulfate (DSS)-induced colitis, decreased TNF in colonic macrophages, and lower corticosterone production in mice. The administration of TNF alleviated the severity of the colitis and was associated with restored corticosterone levels. In conclusion, the data presented in this thesis provide evidence that LPA signaling mediates the intestinal cytokine milieu via GPR35 in CX3CR1+ macrophages.
Advisors: | Hess, Christoph and Niess, Jan Hendrik and Riedel, Cristian |
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Faculties and Departments: | 03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C) 03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C) 03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunobiology (Hess C) |
UniBasel Contributors: | Hess, Christoph and Niess, Jan Hendrik |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 13761 |
Thesis status: | Complete |
Number of Pages: | VII, 111 |
Language: | English |
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edoc DOI: | |
Last Modified: | 27 Jan 2021 16:28 |
Deposited On: | 27 Jan 2021 16:28 |
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