Dulaglutide Modulates the Development of Tissue-Infiltrating Th1/Th17 Cells and the Pathogenicity of Encephalitogenic Th1 Cells in the Central Nervous System.

Hsin-Ying Chiou,Ting-Yi Lin,Ming-Hong Lin,Chun-Lin Chen,Pi-Jung Hsiao,Shiang Chiao,Deng-Chyang Wu,Ming-Wei Lin,Yi-Chen Chen

doi:10.3390/ijms20071584

Abstract

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.

Highlights

GLP-1 is best known as the hormone that induces insulin release during hyperglycemia
We demonstrated that dulaglutide, a well-known GLP-1 RA, potently possesses protective effects on the pathogenesis of autoimmune encephalomyelitis via immune-modulation of CD4-positive T helper cell lineage subsets in the central nervous system (CNS) parenchyma
Our investigations suggested that dulaglutide treatment suppresses the percentage of encephalitogenic Th1/Th17 cell subset and the granulocyte-macrophage-colony-stimulating factor (GM-CSF) production of Th1 cells in the CNS of EAE mice

Summary

Introduction

GLP-1 (glucagon-like peptide-1) is best known as the hormone that induces insulin release during hyperglycemia. Accumulating data revealed that the administration of GLP-1 receptor agonist (GLP-1 RA) alleviates traumatic or ischemic brain damage [2,3] and ameliorates neurodegenerative diseases demonstrated in Alzheimer’s disease (AD) and Parkinson’s disease mice models [4,5] through reduced neuronal cell death and microglial activation. Since the GLP-1 receptor is expressed throughout the brain, GLP-1 RA is considered to have neurotrophic and anti-inflammation effects for CNS diseases [2,3,4,5,6]. It has been proved that the administration of GLP-1 RA delays the disease onset of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by dampening the effects of oxidative stress [7]. Activation of GLP-1 receptor signaling attenuates the clinical severity and incidence of EAE, partially via the inactivation of NF-κB signaling in spinal cord and microglia cells [8]. Whether GLP-1 RA modulates autoreactive T cell subsets and their pathogenicity during neuro-inflammation of EAE remains to be elucidated

Objectives

Methods

Findings

Conclusion