Abstract
BackgroundThe severity and longevity of inflammation is controlled by endogenous counter-regulatory signals. Among them are long-chain polyunsaturated fatty acid (PUFA)-derived lipid mediators, which promote the resolution of inflammation, an active process for returning to tissue homeostasis.ObjectiveTo determine whether endogenous production of lipid-derived resolution agonists is regulated differentially in patients with highly active and less active multiple sclerosis (MS).DesignMatched-pairs study in University hospital Neurology department.PatientsBased on clinical (relapse frequency) and paraclinical (MRI lesions, contrast enhancement) criteria, 10 pairs of age- and sex-matched patients with relapsing-remitting MS were assigned either to a group with highly active or less active MS. Lipid mediators were quantified in serum and cerebrospinal fluid using LC-MS/MS-based lipidomics.ResultsLevels of the key arachidonic (ω-6) and docosahexaenoic acid (ω-6)-derived mediators prostaglandins (PG), leukotrienes, hydroxyeicosatetraenoic acids (HETE) and resolution agonists lipoxin A4 (LXA4), resolvin D1 (RvD1) and neuroprotectin D1 (NPD1) were quantified. In the patient group with highly active MS, 15-HETE and PGE2 were increased, which are products of the 15-lipoxygenase and cyclooxygenase pathways. The proresolution mediator RvD1 was significantly upregulated and NPD1 was detected in the highly active group only. LXA4 levels were not increased in patients with highly active MS.ConclusionsLipid mediator pathways are regulated differentially in the cerebrospinal fluid of MS patients, depending on disease severity. Non-exhaustive or possibly ‘delayed’ resolution pathways may suggest a defective resolution program in patients with highly active MS. Longitudinal analyses are required to hetero-typify this differential resolution capacity, which may be associated with disease progression, longevity and eventual termination.
Highlights
Longitudinal analyses are required to hetero-typify this differential resolution capacity, which may be associated with disease progression, longevity and eventual termination
[1] It is a tightly controlled, directed tissue response orchestrated by cellular and humoral factors such as polyunsaturated fatty acid (PUFA) (omega- 3 (v-3), -6 (v-6))derived lipid mediators. [1,2,3] Early interventional multiple sclerosis (MS) trials supplementing v-3 and v-6 were based on socio-epidemiological studies demonstrating that the risk of MS is high in countries with a high intake of saturated fatty acids and low in countries with a high intake of poly-unsaturated fatty acids (PUFAs)
In the cerebrospinal fluid (CSF), no differences between disease groups were observed in substrate levels group the intermediate, arachidonic acid (AA)-derived molecule 15-hydroxyeicosatetraenoic acid (15-hydroxyeicosatetraenoic acids (HETE)) reached significantly higher levels (4.4 pg/ml 60.8 [mean 6 SEM] vs. 2.2 pg/ml 60.63, P,0.05), and this was the case with the pleiotropic inflammatory mediator prostaglandin E2 (PGE2) (1.27 pg/ml 60.27 vs. 0.65 pg/ml 60.12, P,0.01), Thromboxanes, leukotrienes and prostaglandin
Summary
Resolution of inflammation is an active endogenous process necessary for the termination of inflammatory and autoimmune diseases – inflammation does not just passively fizzle out. [1] It is a tightly controlled, directed tissue response orchestrated by cellular and humoral factors such as PUFA (omega- 3 (v-3), -6 (v-6))derived lipid mediators. [1,2,3] Early interventional MS trials supplementing v-3 and v-6 were based on socio-epidemiological studies demonstrating that the risk of MS is high in countries with a high intake of saturated fatty acids and low in countries with a high intake of poly-unsaturated fatty acids (PUFAs). [4] This remains controversial, since some v-3 and -6-derived lipid mediators have revealed anti-inflammatory and others proinflammatory functions. [1].It is noteworthy that arachidonic acid (AA)-derived prostaglandins such as prostaglandin E2 (PGE2) were originally identified primarily for their potent pro-inflammatory effect, promoting edema formation and oxidative toxicity, but they promote Thelper (TH) and TH17 cell generation, which mediate tissue damage and inflammation. [5] Interference with its receptor suppresses disease progression in mice subjected to experimental autoimmune encephalomyelitis (EAE). [5] Elevated levels of PGE2 were detected in EAE lesions and in the cerebrospinal fluid (CSF) of MS patients. [6] On the other hand, AA is a substrate for the bifunctional, anti-inflammatory and pro-resolutive molecule LXA4. [7,8] The discovery of v-3 and v-6 as substrates for resolution agonists such as lipoxins, protectins and resolvins, which are generated by distinct transcellular pathways, provided a consistent rationale for the underlying biological functions. [1] Deficiencies in these resolution pathways can prolong inflammation and lead to the failure of tissue to return to homeostasis. [1] The recent identification of resolution agonists supports the notion that resolution is an active process independent of inflammation. [2].the role of these molecules in MS pathology remains elusive. Resolution of inflammation is an active endogenous process necessary for the termination of inflammatory and autoimmune diseases – inflammation does not just passively fizzle out. [4] This remains controversial, since some v-3 and -6-derived lipid mediators have revealed anti-inflammatory and others proinflammatory functions. It is noteworthy that arachidonic acid (AA)-derived prostaglandins such as prostaglandin E2 (PGE2) were originally identified primarily for their potent pro-inflammatory effect, promoting edema formation and oxidative toxicity, but they promote Thelper (TH) and TH17 cell generation, which mediate tissue damage and inflammation. We used LC-MS mass spectrometry to investigate the synthesis of the v-3 and v-6-derived resolution agonists in CSF and in serum samples of MS patients with highly and less active disease. Among them are long-chain polyunsaturated fatty acid (PUFA)-derived lipid mediators, which promote the resolution of inflammation, an active process for returning to tissue homeostasis
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