Background and ObjectivesExcessive activation of certain lipid mediator (LM) pathways plays a role in the complexpathogenesis of multiple sclerosis (MS). However, the relationship between bioactive... Show moreBackground and ObjectivesExcessive activation of certain lipid mediator (LM) pathways plays a role in the complexpathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs anddifferent 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-6lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glialfibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients withMS (PwMS) and healthy controls (HCs).MethodsA targeted high-performance liquid chromatography-tandem mass spectrometry approach was usedon plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-basedcohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs werecompared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability(Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates wereincluded in a backward multivariate regression model to identify which LMs best related to disability.ResultsThe study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patientswith progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differedfrom those of patients with RRMS and HCs, particularly patients with PMS showed elevatedlevels 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 biochemicalparameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lowertotal brain (r = −0.24, p = 0.04) and deep gray matter volumes (r = −0.27, p = 0.02) in patientswith PMS and higher lesion volume (r = 0.15, p = 0.03) in all PwMS.DiscussionIn 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 indicatethat, 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 thepotential relevance of ω-6 LMs in the pathogenesis of MS. Show less
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... Show moreThe 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. Show less
Reemst, K.; Broos, J.Y.; Abbink, M.R.; Cimetti, C.; Giera, M.; Kooij, G.; Korosi, A. 2022
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)... Show moreBrain 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(omega)-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 omega 6/omega 3 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 omega 6-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. Show less
BACKGROUND: Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the... Show moreBACKGROUND: Disrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity.OBJECTIVES: This study evaluates the potential of TRAF-STOP treatment in atherosclerosis.METHODS: The effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe-/-) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages.RESULTS: TRAF-STOP treatment of young Apoe-/- mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe-/- mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair "classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-κB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe-/- mice.CONCLUSIONS: TRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis.Published by Elsevier Inc.KEYWORDS: atherosclerosis; drug development; immunology; inflammation; nanotechnology Show less
Laan, L.C.; Williams, A.R.; Stavenhagen, K.; Giera, M.; Kooij, G.; Vlasakov, I.; ... ; I. van die 2017
