Article (Scientific journals)
Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling.
El Abbas, Sophie; Radermecker, Coraline; Bai, Qiang et al.
2019In Mucosal Immunology
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Abstract :
[en] Intestinal epithelial cells (IECs) contribute to the regulation of intestinal homeostasis and inflammation through their interactions with the environment and host immune responses. Yet our understanding of IEC-intrinsic regulatory pathways remains incomplete. Here, we identify the guanine nucleotide exchange factor RABGEF1 as a regulator of intestinal homeostasis and innate pathways dependent on IECs. Mice with IEC-specific Rabgef1 deletion (called Rabgef1(IEC-KO) mice) developed a delayed spontaneous colitis associated with the local upregulation of IEC chemokine expression. In mouse models of colitis based on Interleukin-10 deficiency or dextran sodium sulfate (DSS) exposure, we found that IEC-intrinsic RABGEF1 deficiency exacerbated development of intestinal pathology and dysregulated IEC innate pathways and chemokine expression. Mechanistically, we showed that RABGEF1 deficiency in mouse IECs in vitro was associated with an impairment of early endocytic events, an increased activation of the p38 mitogen-activated protein kinase (MAPK)-dependent pathway, and increased chemokine secretion. Moreover, we provided evidence that the development of spontaneous colitis was dependent on microbiota-derived signals and intrinsic MYD88-dependent pathways in vivo. Our study identifies mouse RABGEF1 as an important regulator of intestinal inflammation, MYD88-dependent IEC-intrinsic signaling, and chemokine production. This suggests that RABGEF1-dependent pathways represent interesting therapeutic targets for inflammatory conditions in the gut.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
El Abbas, Sophie ;  Université de Liège - ULiège > Ingénierie des biosystèmes (Biose) > Echanges Eau-Sol-Plantes
Radermecker, Coraline ;  Université de Liège - ULiège > I3-Immunophysiology
Bai, Qiang  ;  Université de Liège - ULiège > I3-Immunophysiology
BEGUIN, Charline ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Département de médecine interne
Schyns, Joey ;  Université de Liège - ULiège > I3-Immunophysiology
Meunier, Margot ;  Université de Liège - ULiège > Master bioch. & biol. mol. & cel., à fin.
Pirottin, Dimitri ;  Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Département des sciences fonctionnelles (DSF)
Desmet, Christophe  ;  Université de Liège - ULiège > I3-Cellular and Molecular Immunology
Meuwis, Marie-Alice  ;  Centre Hospitalier Universitaire de Liège - CHU > Service de gastroentérologie, hépatologie, onco. digestive
Art, Tatiana ;  Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Phys. neuro-muscul., de l'effort - Méd. sport. des animaux
Louis, Edouard  ;  Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Tam, See-Ying;  Stanford University School of Medicine
Tsai, Mindy;  Stanford University School of Medicine
Bureau, Fabrice ;  Université de Liège - ULiège > Vice-Recteur à la Recherche
Galli, Stephen J.;  Stanford University School of Medicine
Marichal, Thomas  ;  Université de Liège - ULiège > I3-Immunophysiology
More authors (6 more) Less
Language :
English
Title :
Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling.
Publication date :
2019
Journal title :
Mucosal Immunology
ISSN :
1933-0219
eISSN :
1935-3456
Publisher :
Nature Publishing Group, United Kingdom
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 04 November 2019

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