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CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways

Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patien...

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Autores principales: Dicker, Martina, Li, Yingcong, Giles, Daniel A., Verstichel, Greet, Castelan, Viankail Cedillo, Ascui-Gac, Gabriel, Chou, Ting-Fang, Perez-Jeldres, Tamara, Cheroutre, Hilde, Kronenberg, Mitchell
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9652117/
https://www.ncbi.nlm.nih.gov/pubmed/36389671
http://dx.doi.org/10.3389/fimmu.2022.1034648
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author Dicker, Martina
Li, Yingcong
Giles, Daniel A.
Verstichel, Greet
Castelan, Viankail Cedillo
Ascui-Gac, Gabriel
Chou, Ting-Fang
Perez-Jeldres, Tamara
Cheroutre, Hilde
Kronenberg, Mitchell
author_facet Dicker, Martina
Li, Yingcong
Giles, Daniel A.
Verstichel, Greet
Castelan, Viankail Cedillo
Ascui-Gac, Gabriel
Chou, Ting-Fang
Perez-Jeldres, Tamara
Cheroutre, Hilde
Kronenberg, Mitchell
author_sort Dicker, Martina
collection PubMed
description Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183, known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18. Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn’s disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag(-/-) recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag(-/-) mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine.
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spelling pubmed-96521172022-11-15 CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways Dicker, Martina Li, Yingcong Giles, Daniel A. Verstichel, Greet Castelan, Viankail Cedillo Ascui-Gac, Gabriel Chou, Ting-Fang Perez-Jeldres, Tamara Cheroutre, Hilde Kronenberg, Mitchell Front Immunol Immunology Colitis is characterized by an exacerbated intestinal immune response, but the genetic and other mechanisms regulating immune activation remain incompletely understood. In order to identify new pathways leading to colitis, we sought to identify genes with increased expression in the colons of patients that also are near loci identified by genome wide association studies (GWAS) associated with IBD risk. One such SNP, rs9557195 was of particular interest because it is within an intron of G-protein-coupled receptor (GPR) 183, known to be important for lymphocyte migration. Furthermore, this SNP is in close proximity to the gene encoding another G-protein coupled receptor, GPR18. Analyzing publicly available datasets, we found transcripts of GPR183 and GPR18 to be increased in colon biopsies from ulcerative colitis and Crohn’s disease patients, and GPR183 was even more increased in patients resistant to TNF treatment. Expression of both genes also was increased in mouse models of colitis. Therefore, our aim was to understand if increased expression of these GPRs in the intestine is related to disease severity in colitis models. Here we investigated the role of these receptors in the T cell transfer model and the dextran sulfate sodium model. In the T cell transfer model, GPR183 expression on donor T cells, as well as on other cell types in the Rag(-/-) recipients, was not essential for severe colitis induction. Furthermore, deficiency in Rag(-/-) mice for the enzyme that synthesizes a cholesterol metabolite that is a major ligand for GPR183 also did not affect disease. Similarly, lack of GPR18 expression in T cells or other cell types did not affect colitis pathogenesis in the T cell transfer or in the dextran sulfate sodium model. Therefore, despite increased expression of transcripts for these genes in the intestine during inflammation in humans and mice, they are not required for disease severity in mouse models of colitis induced by chemical injury or T cell cytokines, perhaps due to redundancy in mechanisms important for homing and survival of lymphocytes to the inflamed intestine. Frontiers Media S.A. 2022-10-28 /pmc/articles/PMC9652117/ /pubmed/36389671 http://dx.doi.org/10.3389/fimmu.2022.1034648 Text en Copyright © 2022 Dicker, Li, Giles, Verstichel, Castelan, Ascui-Gac, Chou, Perez-Jeldres, Cheroutre and Kronenberg https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Dicker, Martina
Li, Yingcong
Giles, Daniel A.
Verstichel, Greet
Castelan, Viankail Cedillo
Ascui-Gac, Gabriel
Chou, Ting-Fang
Perez-Jeldres, Tamara
Cheroutre, Hilde
Kronenberg, Mitchell
CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
title CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
title_full CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
title_fullStr CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
title_full_unstemmed CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
title_short CD4(+)-mediated colitis in mice is independent of the GPR183 and GPR18 pathways
title_sort cd4(+)-mediated colitis in mice is independent of the gpr183 and gpr18 pathways
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9652117/
https://www.ncbi.nlm.nih.gov/pubmed/36389671
http://dx.doi.org/10.3389/fimmu.2022.1034648
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