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

Authors

Carolina Prado
Alexandra Espinoza
J Eduardo Martínez-Hernández
Joseph Petrosino
Erick Riquelme
Alberto J M Martin
Rodrigo Pacheco

Publication Date

6-1-2023

Journal

\Journal of Neuroinflammation

DOI

10.1186/s12974-023-02815-9

PMID

37264394

PMCID

PMC10233874

PubMedCentral® Posted Date

6-1-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Animals, Receptors, Antigen, T-Cell, alpha-beta, Autoimmunity, Dysbiosis, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Myelin-Oligodendrocyte Glycoprotein, Peptides, Mice, Inbred C57BL, Short-chain fatty acids, GPR43, Mucosal immunity, Gut-brain axis, Neuroinflammation, Experimental autoimmune encephalomyelitis

Abstract

INTRODUCTION: Gut 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.

METHODS: To induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG

RESULTS: Our 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

CONCLUSIONS: These 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.

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