Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System

Abstract

Multiple Sclerosis (MS) is a disease characterized by immune-mediated destruction of central nervous system (CNS) myelin. Current MS therapies aim to block peripheral immune cells from entering the CNS. While these treatments limit new inflammatory activity in the CNS, no treatment effectively prevents long-term disease progression and disability accumulation in MS patients. One explanation for this paradox is that current therapies are ineffective at targeting immune responses already present in the CNS. To this end, we sought to understand the metabolic properties of T cells that mediate ongoing inflammation in the demyelinating CNS. Using experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a well-studied model of MS, we showed that the CD4+ and CD8+ T cells that invade the EAE CNS are highly glycolytic. This elevation of glycolysis is mediated by upregulated expression of the glycolytic machinery, and is essential for inflammatory responses to myelin. Surprisingly, we found that an inhibitor of glyceraldehyde-3 phosphate (GAPDH), 3-bromopyruvic acid (3-BrPa), blocks IFN-γ but not IL-17A production in immune cells isolated from the EAE CNS. Indeed, in vitro studies confirmed that the production of IFN-γ by differentiated Th1 cells is more sensitive to 3-BrPa than the production of IL-17A by Th17 cells. Finally, in transfer models of EAE, 3-BrPa robustly attenuates the encephalitogenic potential of EAE-driving immune cells. These data are one of the first to demonstrate the metabolic properties of T cells in the demyelinating CNS in vivo.

Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis

“…Flow cytometric analyses were performed as described (48). The following Abs were used: TLR4/MD-2 Complex APC (Thermo Fisher Scientific, 17–9924-82), F4/80 Antigen PE (Thermo Fisher Scientific, 12–4801-80), F4/80 Antigen PE Cy7 (Thermo Fisher Scientific, 25–4801-82), CD11b PE Cy7 (Biolegend, 101215), CD11b eFluor 450 (Thermo Fisher Scientific, 48–0112-82), CD11b APC (Thermo Fisher Scientific, 17–0112-82), CD45 PerCP Cy5.5 (Thermo Fisher Scientific, 45–0451-82), CD45 APC (Thermo Fisher Scientific, 17–0451-82), Ly6G APC Cy7 (Tonbo Biosciences, 25–1276), CD19 PE Cy7 (Thermo Fisher Scientific, 25–0193-82), CD4 eFluor 450 (Thermo Fisher Scientific, 48–0042-82), TCRβ (Thermo Fisher Scientific, 12–5961-83), CD8 Alexa Fluor 488 (Thermo Fisher Scientific, 53–0081-82), CD11c PerCP Cy5.5(Thermo Fisher Scientific, 45–0114-82), CD115 APC (Thermo Fisher Scientific, 17–1152-82), Fc Block (Thermo Fisher Scientific, 14–9161-71) and a Zombie Aqua Fixable Viability kit (Biolegend, 423101).…”

Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis

“…Therefore, the relevance of hypoxia-induced HIF-1α stabilization to the underlying glycolytic shift in macrophages requires further investigation. undergo a glycolytic shift in MS (58,59). One reason could be that we studied T cells in the periphery, where the glycolytic shift may occur at a different time point in the disease course in a T cell subset-specific manner.…”

“…One reason could be that we studied T cells in the periphery, where the glycolytic shift may occur at a different time point in the disease course in a T cell subset-specific manner. Also, the pathogenic T cells entering the CNS compartments during EAE exhibit shift to the glycolytic profile as compared with the ones in the blood (58,59).…”

The Suppressive Effect of Butyrate and Bromopyruvate on Inflammatory Cytokine Production and Short Chain Fatty Acid Receptor Expression by Blood Mononuclear Cells in Patients with Behçet's Disease

“…BrPA ameliorates disease severity in a multiple sclerosis mouse model 3 and inhibits arthritis progression in a mouse model 4 . Another metabolic regulator, short chain fatty acids (SCFAs) (e.g., butyrate) affect glucose and lipid metabolism 5 and modify gene expression through interacting with their receptors and regulating histone modifying enzymes 6 .…”

“…A prospective target for controlling inflammation is glycolysis, a pivotal metabolic pathway used by immune cell subtypes to produce inflammatory cytokine 2 . Bromopyruvate (BrPA) inhibits glycolysis through targeting hexokinase 2 and glyceraldehyde 3-phosphate dehydrogenase 3 . Therefore, BrPA ameliorates disease severity in a multiple sclerosis mouse model 3 and inhibits arthritis progression in a mouse model 4 .…”