Search

Background: Multiple sclerosis (MS) is characterized by extensive tissue damage leading to a range of complex symptoms, including physical disability and cognitive dysfunction. Recent work has indicated the clinical relevance of bioactive lipid mediators (LMs), which are known to orchestrate inflammation and its resolution and are deregulated in MS. However, it is unknown whether LM profiles relate to white matter (WM) damage., Objectives: To investigate the potential association between plasma-derived LMs and MRI-quantified WM damage using fractional anisotropy (FA) and grey matter (GM) atrophy in dimethyl fumarate-treated relapsing remitting MS (RRMS) patients., Methods: Severity of FA-based WM damage and GM atrophy was determined in RRMS patients (n = 28) compared to age- and sex-matched controls (n = 31) at treatment initiation (baseline) and after 6 months. Plasma LMs were assessed using HPLC-MS/MS and baseline LMs were correlated to changes in FA and brain volumes., Results: We observed significant WM damage in RRMS patients (mean age 41.4 [SD 9.1]) at baseline and follow-up (z-score=-0.33 and 0.31, respectively) compared to controls (mean age 41.9 [SD 9.5]; p < 0.001 for both comparisons). Patients with severe WM damage showed a decline of thalamic volume (p = 0.02), and this decline correlated (r = 0.51, p < 0.001) with lower baseline levels of 9-HODE. This LM also predicted FA worsening (beta = 0.14, p < 0.001) over time at 6 months., Conclusion: Despite the relatively small sample size, lower baseline levels of the LM 9-HODE correlated with more thalamic atrophy and predicted subsequent worsening of WM damage in RRMS patients., Competing Interests: Declaration of competing interest W.H. Fung: nothing to disclose; M.R. van Lingen was supported during this study by a research grant of Biogen and currently by MEGIN; J.Y. Broos: nothing to disclose; K.H. Lam: nothing to disclose; M. van Dam is supported by a research grant from BMS; W.K. Fung: nothing to disclose; S. Notenboom: nothing to disclose; I. Koubiyr: nothing to disclose; H.E. de Vries: nothing to disclose; B. Jasperse: nothing to disclose; C.E. Teunissen reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831,434). CET has a research contract with Celgene. She serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer; M. Giera: nothing to disclose; J. Killestein received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials. gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials. gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only); H.E. Hulst is an editor of the Multiple Sclerosis Journal controversies sections, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV; E.M.M. Strijbis serves on the editorial board of Frontiers in Neurology and receives research support from Stichting MS Research and ZonMW. She has received speaker fees from Merck and Novartis. M.M. Schoonheim serves on the editorial board of Neurology, Multiple Sclerosis Journal and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck; Gijs Kooij received research support from Biogen, Novartis and Merck., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: In cystic fibrosis (CF), an imbalanced lipid metabolism is associated with lung inflammation. Little is known about the role that specific lipid mediators (LMs) exert in CF lung inflammation, and whether their levels change during early disease progression. Therefore, we measured airway LM profiles of young CF patients, correlating these with disease-associated parameters., Methods: Levels of omega (ω)-3/6 PUFAs and their LM derivatives were determined in bronchoalveolar lavage fluid (BALF) of children with CF ages 1-5 using a targeted high-performance liquid chromatography-tandem mass spectrometry approach. Hierarchical clustering analysis was performed on relative LM levels. Individual relative LM levels were correlated with neutrophilic inflammation (BALF %Neu) and structural lung damage (PRAGMA-CF %Disease). Significant correlations were included in a backward multivariate linear regression model to identify the LMs that are best related to disease progression., Results: A total of 65 BALF samples were analysed for ω-3/6 lipid content. LM profiles clustered into an arachidonic acid (AA)-enriched and a linoleic acid (LA)-enriched sample cluster. AA derivatives like 17-OH-DH-HETE, 5-HETE, 5,15-diHETE, 15-HETE, 15-KETE, LTB 4 and 6-trans-LTB 4 positively correlated with BALF %Neu and/or PRAGMA %Dis. Contrastingly, 9-HoTrE and the LA derivatives 9-HoDE, 9(10)-EpOME, 9(10)-DiHOME, 13-HoDE, 13-oxoODE and 12(13)-EpOME negatively correlated with BALF %Neu and/or PRAGMA %Dis. 6-trans-LTB 4 was the strongest predictor for BALF %Neu. 5-HETE and 15-KETE contributed most to PRAGMA %Dis prediction., Conclusions: Our data provide more insight into the lung lipidome of infants with CF, and show that a shift from LA derivatives to AA derivatives in BALF associates with early CF lung disease progression., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis. For example, disturbances in LM profiles and especially those derived from the ω-6 PUFA arachidonic acid (AA) have been reported in people with MS (PwMS), where they may contribute to the chronicity of neuroinflammatory processes. Moreover, we have previously shown that certain AA-derived LMs also associated with neurodegenerative processes in PwMS, suggesting that AA-derived LMs are involved in more pathological events than solely neuroinflammation. Yet, to date, a comprehensive overview of the contribution of these LMs to MS-associated pathological processes remains elusive., Main Body: This review summarizes and critically evaluates the current body of literature on the eicosanoid biosynthetic pathway and its contribution to key pathological hallmarks of MS during different disease stages. Various parts of the eicosanoid pathway are highlighted, namely, the prostanoid, leukotriene, and hydroxyeicosatetraenoic acids (HETEs) biochemical routes that include specific enzymes of the cyclooxygenases (COXs) and lipoxygenases (LOX) families. In addition, cellular sources of LMs and their potential target cells based on receptor expression profiles will be discussed in the context of MS. Finally, we propose novel therapeutic approaches based on eicosanoid pathway and/or receptor modulation to ultimately target chronic neuroinflammation, demyelination and neurodegeneration in MS., Short Conclusion: The eicosanoid pathway is intrinsically linked to specific aspects of MS pathogenesis. Therefore, we propose that novel intervention strategies, with the aim of accurately modulating the eicosanoid pathway towards the biosynthesis of beneficial LMs, can potentially contribute to more patient- and MS subtype-specific treatment opportunities to combat MS., (© 2024. The Author(s).)

Background and Objectives: Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs and different aspects of CNS-related pathophysiologic processes remains largely unknown. Therefore, in this study, we assessed the association of bioactive LMs belonging to the ω-3/ω-6 lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glial fibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HCs)., Methods: A targeted high-performance liquid chromatography-tandem mass spectrometry approach was used on plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability (Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability., Results: The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differed from those of patients with RRMS and HCs, particularly patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular, 15-hydroxyeicosatetraenoic acid (HETE) ( r = 0.24, p < 0.001) correlated (average r = 0.2, p < 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain ( r = -0.24, p = 0.04) and deep gray matter volumes ( r = -0.27, p = 0.02) in patients with PMS and higher lesion volume ( r = 0.15, p = 0.03) in all PwMS., Discussion: In PwMS of the same birth year, we show that ω-3 and ω-6 LMs are associated with disability, biochemical parameters (sNfL, GFAP), and MRI measures. Furthermore, our findings indicate that, particularly, in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS., (© 2023. The Author(s).)

Brain lipid dysregulation is a hallmark of depression and Alzheimer's disease, also marked by chronic inflammation. Early-life stress (ELS) and dietary intake of polyunsaturated fatty acids (PUFAs) are risk factors for these pathologies and are known to impact inflammatory processes. However, if these early-life factors alter brain lipid homeostasis on the long-term and thereby contribute to this risk remains to be elucidated. We have recently shown that an early diet enriched in omega(ω)-3 PUFAs protected against the long-term negative effects of ELS on cognition and neuroinflammation. Here, we aim to understand if modulation of brain lipid and oxylipin profiles contributes to the detrimental effects of ELS and the protective ones of the diet. We therefore studied if and how ELS and early dietary PUFAs modulate the brain lipid and oxylipin profile, basally as well as in response to an inflammatory challenge, to unmask possible latent effects. Male mice were exposed to ELS via the limited bedding and nesting paradigm, received an early diet with high or low ω6/ω3 ratio (HRD and LRD) and were injected with saline or lipopolysaccharide (LPS) in adulthood. Twenty-four hours later plasma cytokines (Multiplex) and hypothalamic lipids and oxylipins (liquid chromatography tandem mass spectrometry) were measured. ELS exacerbated the LPS-induced increase in IL-6, CXCL1 and CCL2. Both ELS and diet affected the lipid/oxylipin profile long-term. For example, ELS increased diacylglycerol and LRD reduced triacylglycerol, free fatty acids and ceramides. Importantly, the ELS-induced alterations were strongly influenced by the early diet. For example, the ELS-induced decrease in eicosapentaenoic acid was reversed when fed LRD. Similarly, the majority of the LPS-induced alterations were distinct for control and ELS exposed mice and unique for mice fed with LRD or HRD. LPS decreased ceramides and lysophosphotidylcholine, increased hexosylceramides and prostaglandin E 2 , reduced triacylglycerol species and ω6-derived oxylipins only in mice fed LRD and ELS reduced the LPS-induced increase in phosphatidylcholine. These data give further insights into the alterations in brain lipids and oxylipins that might contribute to the detrimental effects of ELS, to the protective ones of LRD and the possible early-origin of brain lipid dyshomeostasis characterizing ELS-related psychopathologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Reemst, Broos, Abbink, Cimetti, Giera, Kooij and Korosi.)

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.