Fatty acids role in multiple sclerosis as "metabokines"

Abstract

Multiple sclerosis (MS), as an autoimmune neurological disease with both genetic and environmental contribution, still lacks effective treatment options among progressive patients, highlighting the need to re-evaluate disease innate properties in search for novel therapeutic targets. Fatty acids (FA) and MS bear an interesting intimate connection. FA and FA metabolism are highly associated with autoimmunity, as the diet-derived circulatory and tissue-resident FAs level and composition can modulate immune cells polarization, differentiation and function, suggesting their broad regulatory role as "metabokines". In addition, FAs are indeed protective factors for blood-brain barrier integrity, crucial contributors of central nervous system (CNS) chronic inflammation and progressive degeneration, as well as important materials for remyelination. The remaining area of ambiguity requires further exploration into this arena to validate the existed phenomenon, develop novel therapies, and confirm the safety and efficacy of therapeutic intervention targeting FA metabolism.

Keywords: Fatty acid metabolism; Immune; Multiple sclerosis; Neurodegeneration.

Fig. 1

FAs as metabokines at a molecular level. SCFAs, MCFAs, LCFAs, and essential PUFAs are mostly obtained from diet, whereas LCFAs can also be synthesized de novo which requires the participation of rate-limiting enzymes, such as acetyl-CoA carboxylases1 (ACC1). The FA β-oxidation process starts with the translocation into mitochondrion assisted by critical transporter carnitine palmitoyl-transferase 1/2 (CPT1/2). The extensive regulatory role of FAs derives from generally five ways of action. (1) FAs are energy substrates that produce NADH, acetyl-CoA, and FADH₂ to support the Krebs cycle and oxidative phosphorylation in the mitochondrion. (2) FAs are responsible for membrane dynamics and through the alteration of FA level and composition regulate local membrane biological functions. (3) FAs activate various membrane and nuclear receptors including GPCRs, TLRs, PPARs, affecting downstream signaling pathways. (4) FAs, especially short-chain FAs, are potent histone deacetylase (HDAC) inhibitors capable of regulating histone or non-histone acetylation to modulate the expression and stability of transcripts and proteins. (5) FAs through metabolism generate downstream lipid mediators, widely participating in the maintenance and resolution of chronic inflammation

Fig. 2

FAs and FA metabolism modulate immune cells’ differentiation and function in MS. a Intracellular FA composition is related to Th17 pathogenicity as the CD5L-prompted rise of unsaturated FA proportion facilitate the maintenance of a non-pathogenic state. b Intracellular FA metabolic pattern witnesses a significant difference among CD4⁺T helper cells which facilitates their diverged differentiation. FA synthesis (FAS) initiated by ACC1 favors the differentiation towards pathogenic Th17, while FA metabolism indispensable of CPT1/2 induces the differentiation towards protective Treg. Extracellular SCFA, LCFA, and PUFA as metabokines manifest broad immunomodulatory property (c–e). c SCFAs, by manipulating protein acetylation and inner metabolic state, enhance Treg differentiation, and transform various innate immune cells into a more protective state and, meanwhile, reduce the number and function of Th17 and Th1 cells. Interestingly, SCFAs regulate B lymphocytes function in a dose-dependent manner. d Adipose-resident oleic acid, as a kind of LCFA, increases FA oxidation (FAO) of Treg, leading to a boost of its regulative function. e PUFAs, especially omega-3 DHA, induce the CD4⁺T naïve cells differentiation into Treg while dampening proinflammatory cytokine secretion of Th17, Th1 cells. Omega-3 PUFAs also exhibit modulatory role for innate immune cells, favoring the resolution of inflammation. MAC macrophage, MAST mast cell, NEUT neutrophil

Fig. 3

FAs with multifaceted roles in MS CNS pathogenesis. a FAs, by inhibiting the inflammation-induced MNCs activation and migration, as well as by alleviating oxidative stress of endothelial cells, help to preserve BBB integrity during the pathogenic state. b FA metabolism modulates the polarization of microglia, which are critical contributors of MS late-stage CNS lesions. c FAs regulate CNS resident glia by introducing them to an anti-inflammatory and pro-neurogenic state. d FAs reduce neuron apoptosis and CNS oxidative stress. e FAs promote remyelination by providing raw materials, recruiting stem cells and progenitor cells, and by favoring oligodendrocytes differentiation and metabolic homeostasis. BBB blood–brain barrier, CNS central nervous system, MNC mononuclear cell

Fig. 4

Attempts of targeting FAs and FA metabolism in MS animal models. A blockage of FAs chaperones or critical FAS enzymes, including fatty acid binding protein 4/5 (FABP4/5), FABP5/7, fatty acid synthase (FASN) and ACC1, by inducing FAO in peripheral immune system, manages to restore the proper balance of Treg–Th1/17 axis, mitigating EAE severity. SCFAs and omega-3 PUFAs including DHA or EPA treatments are also able to reduce EAE clinical score by manipulating CD4⁺T cells differentiation and subtype function. The blockage of CD5L, an inhibitor of FASN function, serves to increase SFA/PUFA ratio in Th17 cells, favoring a more pathogenic phenotype, therefore, aggravating EAE symptoms. Methyl acetate treatment by reducing Th1, Th17 chemotaxis and CNS infiltration mitigates EAE. Valproic acid (VPA) supplementation alleviates EAE by promoting T cells apoptosis. Valeric acid supplementation boosts Breg function which leads to EAE remission. In CNS pathogenic state, omega-3 PUFAs and butyrate either by increasing anti-inflammatory bio-mediators or by directly supporting oligodendrocyte precursor cell (OPC) differentiation, alleviate cuprizone-induced demyelination. Oleic acid supplementation relieves EAE symptoms by reducing oxidative stress as the decrease of GSH/GSSG ratio. VPA mitigates EAE by reducing retinal ganglion cells (RGC) apoptosis and by recruiting neural stem or progenitor cells (NSC, NPC). Critical FAO enzyme CPT1 inhibitor and VPA administration alleviate EAE demyelination by reducing FA loss while boosting FA and cholesterol biosynthesis. EAE experimental autoimmune encephalomyelitis, PUFA poly-unsaturated fatty acid, SFA saturated fatty acid

Fig. 5

Proposed role of FA and FA metabolism in MS patients. First, FAs can serve as biomarkers of disease activity and therapeutic efficacy. Multiple FAs serological concentration can reflect disease activity, including intestinal barrier permeability, Treg–Th1 axis balance and EDSS score. A longitudinal cohort of pregnant MS patients indicates the predictive value of FAs ratio in determining risk of relapse. Moreover, after DMF treatment, drop of lymphocyte counts correlates the fluctuation of serological SFA and MUFA level. Second, FAs intake or metabolic state contributes to MS susceptibility. MS patients, long before onset, acquire a unique FA serological profile. Gut microbiome data indicates a preferentially decrease of SCFAs-producing bacteria in MS patients. Several FA metabolism-related enzyme single nucleotide polymorphisms (SNPs), and PUFAs intake patterns are related to MS incidence. Third, FAs are potential MS therapeutic targets. As FAs and related bio-mediators level are altered among MS patients, adequate supplementation helps to reduce MS incidence risk, annual relapse rate (ARR), clinical score, CNS pathology and quality of life (QOL). Fourth, FAs biological compositions are constituents of MS metabolic memory that would influence immune system. A significantly decreased level of adipose-resident oleic acid among MS patients leads to a pro-inflammatory transcriptional profile of Treg cells, which can be reversed by oleic acid supplementation. CIS clinically isolated syndrome, EDSS Expanded Disability Status Scale, FADS fatty acid desaturase