International Journal of Molecular Sciences Review New Insights into Multiple Sclerosis Mechanisms: Lipids on the Track to Control Inflammation and Neurodegeneration Maria Podbielska 1,2,* , Joan O’Keeffe 3 and Anna Pokryszko-Dragan 4 1 Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA 2 Laboratory of Microbiome Immunobiology, Ludwik Hirszfeld Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland 3 Department of Analytical, Biopharmaceutical and Medical Sciences, School of Science & Computing, Galway-Mayo Institute of Technology, Galway, Ireland; [email protected] 4 Department of Neurology, Wroclaw Medical University, 50-556 Wroclaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-71-370-9912 Abstract: Multiple sclerosis (MS) is a central nervous system disease with complex pathogenesis, including two main processes: immune-mediated inflammatory demyelination and progressive degeneration with axonal loss. Despite recent progress in our understanding and management of MS, availability of sensitive and specific biomarkers for these both processes, as well as neuroprotec- tive therapeutic options targeted at progressive phase of disease, are still being sought. Given their abundance in the myelin sheath, lipids are believed to play a central role in underlying immunopatho- genesis in MS and seem to be a promising subject of investigation in this field. On the basis of our previous research and a review of the literature, we discuss the current understanding of lipid-related mechanisms involved in active relapse, remission, and progression of MS. These insights highlight Citation: Podbielska, M.; O’Keeffe, J.; potential usefulness of lipid markers in prediction or monitoring the course of MS, particularly in its Pokryszko-Dragan, A. New Insights progressive stage, still insufficiently addressed. Furthermore, they raise hope for new, effective, and into Multiple Sclerosis Mechanisms: stage-specific treatment options, involving lipids as targets or carriers of therapeutic agents. Lipids on the Track to Control Inflammation and Neurodegeneration. Keywords: central nervous system; lipids; inflammation; lipidomics; MS biomarkers; MS therapy; Int. J. Mol. Sci. 2021, 22, 7319. https://doi.org/10.3390/ijms22147319 MS mechanisms; multiple sclerosis; neurodegeneration; neurological diseases Academic Editor: Barbara Mroczko Received: 19 May 2021 1. Introduction Accepted: 2 July 2021 Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the Published: 7 July 2021 central nervous system (CNS). The multifocal CNS injury results in MS lesion forma- tion, designated as demyelinating plaques. Histopathological examination of CNS tissues Publisher’s Note: MDPI stays neutral indicates infiltration of T lymphocytes, B cells, and macrophages, as well as oligoden- with regard to jurisdictional claims in drocyte damage and axonal degeneration (axonopathy). MS usually exhibits multiphase published maps and institutional affil- course with periods of exacerbations (relapses) and improvement (remission)—typical iations. for relapsing–remitting MS (RRMS) subtype. However, in later stages of the disease, the majority of patients present a gradual progression of neurological symptoms and disability, transforming into secondary progressive (SPMS) form. A small percentage of patients develop primary progressive (PPMS) course from the disease onset. The more recent un- Copyright: © 2021 by the authors. derstanding of MS disease course assumes distinguishing two main phases of the disease: Licensee MDPI, Basel, Switzerland. active and progressive/inactive, which may be temporarily overlapping [1]. This article is an open access article MS-related damage to the CNS is thought to be mediated by two overlapping pro- distributed under the terms and cesses: inflammatory demyelination and progressive neurodegeneration [2]. Both processes conditions of the Creative Commons were shown to be initiated at the disease onset, but they develop with different dynamics: Attribution (CC BY) license (https:// the peak of inflammatory activity occurs in the early stages of MS, while neurodegeneration creativecommons.org/licenses/by/ with axonal loss is gradually escalating towards more advanced progressive stages [3]. It 4.0/). Int. J. Mol. Sci. 2021, 22, 7319. https://doi.org/10.3390/ijms22147319 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 7319 2 of 29 Int. J. Mol. Sci. 2021, 22, x 2 of 31 dynamics:is also suggested the peak of inflammatory that in MS activity patients occurs two in the types early ofstages inflammation of MS, while neu- (focal and diffuse) occur, rodegenerationwhich develop with inaxonal parallel loss is gradually but partially escalating independent towards more fromadvanced each progres- other [4]. sive stagesOver [3]. the It is past also suggested decade, that great in MS progress patients intwo understanding types of inflammation the (focal role of the immune system, and diffuse) occur, which develop in parallel but partially independent from each other [4].both “innate immune system” and “adaptive immune system”, in MS has been made, linkingOver themthe past to decade, different great stagesprogress ofin theunderstanding disease (Figurethe role of1). the Thus, immune while sys- the adaptive immune tem,system both “innate is mainly immune involved system” inand the “adaptive acute immune inflammatory system”, in events, MS has been innate made, immunity plays a major linking them to different stages of the disease (Figure 1). Thus, while the adaptive immune systemrole in is mainly progressive involved phasein the acute of MS.inflammatory However, events, the innate mechanisms immunity plays resulting a ma- in the escalation of jorthe role autoimmune in progressive phase response of MS. However, and MS-related the mechanisms CNS resulting damage in the are escalation complex and have not been ofthus the autoimmune far fully elucidated. response and MS-related It is widely CNS believeddamage are thatcomplex MS and develops have not been in genetically susceptible thusindividuals, far fully elucidated. with contribution It is widely believed of environmental that MS develops in factors genetically (infectious susceptible pathogens, exposure to individuals, with contribution of environmental factors (infectious pathogens, exposure tosunlight, sunlight, vitamin vitamin D3 level, D3 level, hormonal hormonal dysregulation, dysregulation, stress, etc.). stress, etc.). FigureFigure 1. The 1. The core of core multiple of multiple sclerosis (MS) sclerosis background (MS) is associated background with disturbed, is associated autoreactive with disturbed, autoreactive activity of both the innate and adaptive immunological system. As a result of complex interplay betweenactivity genetic of both and environmental the innate factors, and adaptive pools of auto-reactive immunological T cells are activated system. and As enter a resultthe of complex interplay centralbetween nervous genetic system and(CNS) environmental through the disrupte factors,d blood–brain pools barrier of auto-reactive(BBB). Their entry Tis facil- cells are activated and enter itated, i.e., by enhanced expression of endothelial adhesion molecules (ICAM-1, VCAM-1) and ma- trixthe metalloproteinases central nervous (MMP-2, system MMP-9). (CNS) An activati throughon of glial the cells disrupted further contributes blood–brain to pro-in- barrier (BBB). Their entry flammatoryis facilitated, properties i.e., of by the enhanced CNS environment. expression Multiple ofmechanisms endothelial of immune-mediated adhesion molecules injury (ICAM-1, VCAM-1) of myelin and axons have been postulated: cytokine-mediated damage, digestion of surface myelin antigensand matrix by macrophages, metalloproteinases antibody-dependent (MMP-2, and complement-mediated MMP-9). An activation cytotoxicity, of and glial direct cells further contributes to cytotoxicpro-inflammatory attack by CD8+ T properties cells. Parallel of to theinflammatory CNS environment. activity, there is slowly Multiple expanding mechanisms neuro- of immune-mediated degenerative injury with axonopathy. The main contributing factors include: toxic metabolites injury of myelin and axons have been postulated: cytokine-mediated damage, digestion of surface myelin antigens by macrophages, antibody-dependent and complement-mediated cytotoxicity, and + direct cytotoxic attack by CD8 T cells. Parallel to inflammatory activity, there is slowly expanding neurodegenerative injury with axonopathy. The main contributing factors include: toxic metabolites (ROS, NO, RNS), mitochondrial and peroxysomal dysfunction with energetic deficit as well as disturbed ionic balance, and emerging pro-apoptotic activity. Abbreviations: BDNF—brain-derived neurotrophic factor, DAMP—danger associated molecular pattern, DC—dendritic cell, IFN-γ— interferon γ, IL—interleukin, iNKT cells—invariant natural killer T cells, MBP—myelin basic protein, NGF—nerve growth factor, NLR—NOD-like receptors, PAMP—pathogen-associated molecular pattern, TGF-β—transforming growth factor β, Th—T helper, TLR—Toll-like receptor, TNF-α— tumor necrosis factor α. Adapted from [5]. A great individual variability in clinical presentation in the population of MS patients, presumably determined by differences in dynamics and profile of immune-mediated Int. J. Mol. Sci. 2021, 22, 7319 3 of 29 underlying processes [6], makes