The Heteromeric Complex Formed by Dopamine Receptor D5 and CCR9 Leads the Gut Homing of CD4+ T Cells Upon InflammationSummary
| Autor: | Gemma Navarro, Alvaro Lladser, Javier Campos, Alexandra Espinoza, Francisco Contreras, Carolina Prado, Iu Raïch, Rodrigo Pacheco, Rafael Franco, Francisco Osorio-Barrios, Ernesto Lopez, Valentina Ugalde |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
RT-PCR
reverse-transcription polymerase chain reaction 0301 basic medicine CD4-Positive T-Lymphocytes RLuc Renilla luciferase Adoptive cell transfer PLA proximity ligation assays RC799-869 Ab antibody Jurkat Cells ZAq Zombie Aqua 0302 clinical medicine Intestinal mucosa Cell Movement RA retinoic acid Receptors Dopamine D5 DSS dextran sodium sulfate Intestinal Mucosa Phosphorylation Receptor Original Research IBD inflammatory bowel disease Chemistry Integrin beta1 Dopaminergic Gastroenterology Diseases of the digestive system. Gastroenterology Colitis Inflamació DRD5 dopamine receptor D5 Cell biology Intestines Editorial Chemokine Receptors 030211 gastroenterology & hepatology FITC fluorescein isothiocyanate medicine.symptom Signal Transduction Gut Tropism CCR9 C-C chemokine receptor 9 DR dopamine receptor MAP Kinase Signaling System T Cell Migration Cèl·lules Cells PBS phosphate-buffered saline Inflammation Models Biological Tropism cDNA complementary DNA 03 medical and health sciences Receptors CCR Immune system FBS fetal bovine serum MLN mesenteric lymph node Dopamine receptor D5 CD Crohn’s disease medicine Animals Humans Amino Acid Sequence Inflammatory Colitis mAb monoclonal antibody BRET bioluminescence resonance energy transfer Th T helper Cell Proliferation Hepatology Dopaminergic Regulation AlloPC-Cy7 AlloPC-cyanine 7 cLP colonic lamina propria CTV cell trace violet AlloPC allophycocyanin Inflammatory Bowel Diseases YFP yellow fluorescent protein IL interleukin Gastrointestinal Tract Mice Inbred C57BL UC ulcerative colitis 030104 developmental biology BATF B cell–activating transcription factor GPCR G protein–coupled receptor BSA bovine serum albumin G Protein–Coupled Receptors Heteromers Protein Multimerization Peptides TM transmembrane Homing (hematopoietic) |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 2, Pp 489-506 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | Background and aims: CD4+ T cells constitute central players in inflammatory bowel diseases (IBDs), driving inflammation in the gut mucosa. Current evidence indicates that CCR9 and the integrin α4β7 are necessary and sufficient to imprint colonic homing on CD4+ T cells upon inflammation. Interestingly, dopaminergic signaling has been previously involved in leukocyte homing. Despite dopamine levels are strongly reduced in the inflamed gut mucosa, the role of dopamine in the gut homing of T cells remains unknown. Here, we study how dopaminergic signaling affects T cells upon gut inflammation. Methods: Gut inflammation was induced by transfer of naïve T cells into Rag1-/- mice or by administration of dextran sodium sulfate. T cell migration and differentiation were evaluated by adoptive transfer of congenic lymphocytes followed by flow cytometry analysis. Protein interaction was studied by bioluminescence resonance energy transfer analysis, bimolecular fluorescence complementation, and in situ proximity ligation assays. Results: We show the surface receptor providing colonic tropism to effector CD4+ T cells upon inflammation is not CCR9 but the complex formed by CCR9 and the dopamine receptor D5 (DRD5). Assembly of the heteromeric complex was demonstrated in vitro and in vivo using samples from mouse and human origin. The CCR9:DRD5 heteroreceptor was upregulated in the intestinal mucosa of IBD patients. Signaling assays confirmed that complexes behave differently than individual receptors. Remarkably, the disruption of CCR9:DRD5 assembly attenuated the recruitment of CD4+ T cells into the colonic mucosa. Conclusions: Our findings describe a key homing receptor involved in gut inflammation and introduce a new cell surface module in immune cells: macromolecular complexes formed by G protein-coupled receptors integrating the sensing of multiple molecular cues. Keywords: Chemokine Receptors; Dopaminergic Regulation; G Protein-Coupled Receptors Heteromers; Gut Tropism; Inflammatory Bowel Diseases; Inflammatory Colitis; T Cell Migration. |
| Databáze: | OpenAIRE |
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