Interaction between Th17 and central nervous system in multiple sclerosis

Abstract

Image 1.

Keywords: CNS; Cytokine network; Immune therapy; Multiple sclerosis; Th17.

Graphical abstract

Fig. 1

The cellular immune and metabolic regulation of Th17 differentiation in MS. The ligation of IL-6 and IL-6R, IL-23 and IL-23R, TREM-2 and p-ZAP70 results in the phosphorylation of STAT3. The phosphorated-STAT3 binds to the promoter region, CNS6, and CNS9 regions in Rorc to promote the differentiation and maturation of Th17 cells. The p-STAT3 induced by IL-23 inhibit the expression of CD5L/AIM and control the synthesis of fatty acid. In animal model of MS, low expression of CD5L/AIM in the local Th17 cells decreases the cellular PUFA and increases hydroxycholesterols. These hydroxycholesterols can interact with RORγt and promote the expression of Il17 and Il-23r. Transcriptional factors including EGR2, Runx1, BATF, and IRF-4 promote the RORγt transcription and enhance Th17 cell differentiation. The mitochondrial OXPHOS activates mTORC1-HIF-1 pathway and enhances the activation of STAT3. Additionally, OXPHOS also promotes the Th17 cell differentiation in a BATF-dependent manner through TCR signaling regulation. Glutaminase1 increases HIF-1 and promotes glycolysis, contributing to the differentiation of Th17 cells, while CoA combining with PKMZ inhibits glycolysis.

Fig. 2

The interaction between Th17 cells, VECs, neurons, and glial cells in MS. During the migration through the blood-brain barrier (BBB), Th17 cells express IL-17 to upregulate CCL2, CXCL1, and ROS in vascular endothelial cells (VECs). IL-17 and TNF cause the activation of astrocytes which express CCL20, IL-1β, and other cytokines to expand Th17 cell differentiation. IL-17 blocks the maturation from OPCs to oligodendrocytes and impairs oligodendrocytes, thus causing demyelination. Th17 cells damage neurons by producing IL-17 to increase its Ca²⁺ and forming immune-neuronal synapses. IL-17 produced by Th17 cells upregulates MHC Ⅱ in microglia which present myelin-specific antigen and express IL-23 to stimulate Th17 cells, thus resulting in demyelination during MS development.