GPR43 stimulation on TCRαβ+ intraepithelial colonic lymphocytes inhibits the recruitment of encephalitogenic T-cells into the central nervous system and attenuates the development of autoimmunity

Journal of Neuroinflammation

Research

Joseph Petrosino¹  Alexandra Espinoza²  Carolina Prado³  Rodrigo Pacheco³  J. Eduardo Martínez-Hernández⁴  Alberto J. M. Martin⁵  Erick Riquelme⁶ 

[1] Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA;Laboratorio de Neuroinmunología, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida Del Valle Norte #725, 8580702, Huechuraba, Santiago, Chile;Laboratorio de Neuroinmunología, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida Del Valle Norte #725, 8580702, Huechuraba, Santiago, Chile;Facultad de Medicina y Ciencia, Universidad San Sebastián, 7510156, Providencia, Santiago, Chile;Laboratorio de Redes Biológicas, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida Del Valle Norte #725, 8580702, Huechuraba, Santiago, Chile;Agriaquaculture Nutritional Genomic Center, Temuco, Chile;Laboratorio de Redes Biológicas, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Avenida Del Valle Norte #725, 8580702, Huechuraba, Santiago, Chile;Escuela de Ingeniería, Facultad de Ingeniería Arquitectura y Diseño, Universidad San Sebastián, Providencia, Chile;Respiratory Diseases Department, Faculty of Medicine, Pontifical Catholic University of Chile, Santiago, Chile;

关键词: Short-chain fatty acids;    GPR43;    Mucosal immunity;    Gut-brain axis;    Neuroinflammation;    Experimental autoimmune encephalomyelitis;   

DOI  :  10.1186/s12974-023-02815-9

 received in 2022-12-22, accepted in 2023-05-22,  发布年份 2023

来源: Springer

【 摘 要 】

IntroductionGut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity.MethodsTo induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG35-55 peptide). To address the effects of GPR43 stimulation on colonic TCRαβ+ T-cells upon CNS autoimmunity, mucosal lymphocytes were isolated and stimulated with a selective GPR43 agonist ex vivo and then transferred into congenic mice undergoing EAE. Several subsets of lymphocytes infiltrating the CNS or those present in the gut epithelium and gut lamina propria were analysed by flow cytometry. In vitro migration assays were conducted with mucosal T-cells using transwells.ResultsOur results show a sharp and selective reduction of intestinal propionate at the peak of EAE development, accompanied by increased IFN-γ and decreased IL-22 in the colonic mucosa. Further analyses indicated that GPR43 was the primary SCFAs receptor expressed on T-cells, which was downregulated on colonic TCRαβ+ T-cells upon CNS autoimmunity. The pharmacologic stimulation of GPR43 increased the anti-inflammatory function and reduced the pro-inflammatory features in several TCRαβ+ T-cell subsets in the colonic mucosa upon EAE development. Furthermore, GPR43 stimulation induced the arrest of CNS-autoreactive T-cells in the colonic lamina propria, thus avoiding their infiltration into the CNS and dampening the disease development. Mechanistic analyses revealed that GPR43-stimulation on mucosal TCRαβ+ T-cells inhibits their CXCR3-mediated migration towards CXCL11, which is released from the CNS upon neuroinflammation.ConclusionsThese findings provide a novel mechanism involved in the gut-brain axis by which bacterial-derived products secreted in the gut mucosa might control the CNS tropism of autoreactive T-cells. Moreover, this study shows GPR43 expressed on T-cells as a promising therapeutic target for CNS autoimmunity.

【 授权许可】

CC BY   
© The Author(s) 2023

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