Impact of Exercise on Immunometabolism in Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms' mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

Keywords: CNS; EAE; amino acid; exercise; fatty acid metabolism; glycolysis; immunometabolism; mitochondria; multiple sclerosis; oxidative phosphorylation.

Figure 1

An outline of MS immunopathology: MS results from breakdown of the blood-brain barrier (BBB) leading to migration of immune cells into the central nervous system (CNS). These immune cells secrete a range of pro-inflammatory cytokines as well as reactive oxygen and nitrogen species (ROS/RNS), which induce inflammation, formation of sclerotic plaques (lesions), demyelination and axonal degradation. Pathological immune cells in MS include innate immune cells like activated macrophages and resident microglia, autoreactive T-cells (that are activated at peripheral sites, potentially through molecular mimicry, bystander activation or the co-expression of T-cell receptors (TCRs) with different specificities [2]) and antibody producing B-cells. (APC: Antigen-presenting cell); Image made in Biorender^TM (BioRender.com).

Figure 2

An outline of key metabolic pathways altered upon immune cell activation: Cells modify specific metabolic pathways depending on their requirements for activation, growth, development or survival. This capability to shift utilisation of various pathways to generate energy from nutrients like carbohydrates (e.g., glucose), proteins and fats is termed immunometabolism. ATP: Adenosine Triphosphate; LDH: Lactate Dehydrogenase; MCT: Monocarboxylate Transporter; HK: Hexokinase; G-6P: Glucose-6-Phosphate; PGI: Phosphoglucoisomerase; F-6P: Fructose-6-phosphate; PFK1: Phosphofructokinase 1; F-1,6 BP: Fructose 1,6-Bisphosphate; ALDA Aldolase; G-3P: Glyceraldehyde-3-phosphate; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; 1,3 BPG: 1,3-bisphosphoglycerate; PEP: Phosphoenolpyruvate; PK: Pyruvate Kinase; G6PD: Glucose-6-phosphate dehydrogenase; R5BP: Ribulose 1,5-bisphosphate; NADPH: Nicotinamide adenine dinucleotide phosphate; Acetyl CoA: Acetyl coenzyme A; ACLY: ATP citrate lyase; ACC: Acetyl-CoA carboxylase; FAS: Fatty acid synthase; HMGACR: HMG-CoA reductase; IDH: Isocitrate dehydrogenase; SDH: Succinate dehydrogenase; FH: Fumarase; MDH: Malate dehydrogenase; OAA: Oxaloacetate; CS: Citrate Synthase; ACS: Acetyl CoA Synthase; FAO: Fatty Acid Oxidation; CPT: Carnitine palmitoyltransferase; GLUD: Glutamate dehydrogenase; GLS: Glutaminase, NADH: Nicotinamide adenine dinucleotide; FADH2: Flavin adenine dinucleotide, CoQ: Coenzyme Q; Cyt C: Cytochrome C; TCA: Tricarboxylic Acid Cycle. Image made in Biorender^TM.

Figure 3

A summary of the impact glycolysis has on cells in MS: Glycolysis is a major pathway via which glucose is metabolised and generally is involved in activation of various immune cell subsets that are pathological in MS. Activation of immune cells such as in monocytes, macrophages and CD8+ T cells, and differentiation of CD4+ T-cell subsets, such as T_H1 and T_H17, leads to production of pro-inflammatory cytokines and cytotoxic granules. IL: Interleukin; TNF: Tumor Necrosis Factor; IFN: Interferon; TH: T Helper Cell; TP1: Topoisomerase 1; GAPDH: Glyceraldehyde 3-phosphate dehydrogenase; MS: Multiple Sclerosis. Image made in Biorender^TM.

Figure 4

Fatty Acid metabolism in immune cell subtypes: Fatty acid oxidation (FAO) is primarily utilised by immunoregulatory cell types such as anti-inflammatory M2-like macrophages and T_reg cells to boost oxidative respiration by their mitochondria, whereas synthesis of fatty acids and cholesterol is increased in effector T-cells and B-cells for differentiation and development as well as in M1-like proinflammatory macrophages. Image made in Biorender^TM.

Figure 5

Mitochondrial metabolism in determining macrophage phenotype: Inflammatory macrophages constitute one of the largest immune cell infiltrates in CNS in MS. Proinflammatory macrophages have a distinct metabolic profile where they have reduced ATP production via OxPhos, altered TCA cycle metabolites (such as enhanced citrate and succinate levels), and have upregulated glycolysis and fatty acid synthesis pathways via mammalian target of Rapamycin (mTOR) activation. Such dysregulated mitochondrial metabolism allows these cells to be highly bactericidal by secreting inflammatory cytokines and ROS. On the other hands, immunoregulatory macrophages rely predominantly on TCA cycle and electron transport chain mediated OxPhos to generate ATP. This is aided by increased FAO via 5’ AMP-activated protein kinase (AMPK) activation. Image adapted from Biorender^TM.

Figure 6

Impact of exercise on immune-inflammatory response and metabolic function. Regular aerobic/endurance exercise has shown to induce a tolerogenic glucose state, which is associated with a state of immunomodulation through changes in amino acid metabolism (e.g., increased kyunrenic acid and glutamate oxidation) and nutrient sensor pathways (increased AMPK:mTOR ratio). This induces increases mitochondrial biogenesis and oxidative respiration at the mitochondria at least partly through increased fatty acid oxidation (FAO) and decreased fatty acid synthesis (FAS). This impacts on various organs and cells, including (1) higher myokine IL-6 secretion by skeletal muscle tissue; (2) Decreased proinflammatory macrophage and effector T cell number and cytotoxic activity; (3) Decreased ROS and proinflammatory cytokine production by innate immune cells, as well as an increased antioxidant response; (4) increase in T_reg number and function; (5) decrease in leptin secretion (likely due to reduced fat mass) and increase in adiponectin secretion, and lower proinflammatory M1-like macrophage infiltration. Image made in Biorender^TM.