Specialized Pro-Resolving Mediators in Neuroinflammation: Overview of Studies and Perspectives of Clinical Applications

Valente, Mariarosaria; Dentoni, Marta; Bellizzi, Fabrizio; Kuris, Fedra; Gigli, Gian Luigi

doi:10.3390/molecules27154836

Cited by 18 publications

(11 citation statements)

References 110 publications

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“…The failure to transition from the production of PLMs to SPMs leads to defective resolution of inflammation, contributing to the progression of various chronic inflammatory disorders 60,61 . In individuals with alcohol use disorder (AUD) or AH, serum profiles of bioactive lipid metabolites derived from the oxidation of ω-6 and ω-3 PUFAs are profoundly altered as determined by LC-MS/MS 62 .…”

Section: Discussionmentioning

confidence: 99%

Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis

Li,

Xia,

Yang

et al. 2023

Preprint

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BackgroundChronic excessive alcohol consumption leads to a spectrum of alcohol-associated liver diseases (ALD), including alcoholic hepatitis (AH). AH is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is an actively regulated process, primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from ω-6 and ω-3 poly-unsaturated fatty acids (PUFAs). We investigated the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the ω-6 and ω-3 PUFA metabolic pathways and examined the impact of alcohol abstinence on rectifying the dysregulated biosynthesis of PLMs and SPMs in AH patients.MethodsLC-MS/MS and ELISA were used to quantify levels of bioactive lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and various markers of inflammatory cascade andmicrobial translocation. Furthermore, we conducted a longitudinal study to track changes in levels of LMs over 6- and 12-month follow-ups in AH patients who underwent alcohol abstinence.ResultsAH patients exhibited significantly higher plasma levels of ω-6 PLMs (PGD2and LTB4) and SPM RvE1 compared to HDCs and/or HCs. Conversely, key SPMs such as LXA4, RvD1, and several precursors in the ω-3 pathway were significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity, clinical parameters, and various inflammatory cytokines. In particular, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score, suggesting its potential utility as an indicator of disease severity in AH patients. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence.ConclusionOur study reveals significant dysregulation in the levels of PLM metabolites and anti-inflammatory SPMs in both ω-6 and ω-3 PUFA pathways in AH patients. This disrupted biosynthesis, characterized by an overabundance of PLMs and a deficiency in SPMs, is linked to the heightened inflammation observed in AH patients. Importantly, our findings suggest an important role of alcohol abstinence in restoring the balance of these LMs and the potential therapeutic benefits of SPM supplements in alleviating the inflammatory cascade in AH patients.

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Section: Discussionmentioning

confidence: 99%

Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis

Li,

Xia,

Yang

et al. 2023

Preprint

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“…Microglia express a wide array of SPM receptors, whose activation encourages anti-inflammatory responses and homeostatic restoration. Thus, omega-3 PUFA-derived SPMs effectively balance the neuroinflammatory and pain processes in the interaction between glial cells and neurons ( 18 ).…”

Section: Omega-3 Fatty Acid and Its Neuroimmunological Effectmentioning

confidence: 99%

“…Moreover, various specialized pro-resolving mediators (SPMs) produced from omega-3 PUFAs help in moderating undue neuroinflammatory responses and inflammatory pain, facilitating communication between glial cells and neurons. This could significantly contribute to the mitigation of migraine symptoms ( 18 ). This paper aims to outline the neuroimmunological actions of omega-3 PUFAs in migraine prevention and offer an up-to-date review on this subject.…”

Section: Introductionmentioning

confidence: 99%

Neuroimmunological effects of omega-3 fatty acids on migraine: a review

Chen,

Yang,

Tsai

et al. 2024

Front. Neurol.

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Migraine is a highly prevalent disease worldwide, imposing enormous clinical and economic burdens on individuals and societies. Current treatments exhibit limited efficacy and acceptability, highlighting the need for more effective and safety prophylactic approaches, including the use of nutraceuticals for migraine treatment. Migraine involves interactions within the central and peripheral nervous systems, with significant activation and sensitization of the trigeminovascular system (TVS) in pain generation and transmission. The condition is influenced by genetic predispositions and environmental factors, leading to altered sensory processing. The neuroinflammatory response is increasingly recognized as a key event underpinning the pathophysiology of migraine, involving a complex neuro-glio-vascular interplay. This interplay is partially mediated by neuropeptides such as calcitonin gene receptor peptide (CGRP), pituitary adenylate cyclase activating polypeptide (PACAP) and/or cortical spreading depression (CSD) and involves oxidative stress, mitochondrial dysfunction, nucleotide-binding domain-like receptor family pyrin domain containing-3 (NLRP3) inflammasome formation, activated microglia, and reactive astrocytes. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), crucial for the nervous system, mediate various physiological functions. Omega-3 PUFAs offer cardiovascular, neurological, and psychiatric benefits due to their potent anti-inflammatory, anti-nociceptive, antioxidant, and neuromodulatory properties, which modulate neuroinflammation, neurogenic inflammation, pain transmission, enhance mitochondrial stability, and mood regulation. Moreover, specialized pro-resolving mediators (SPMs), a class of PUFA-derived lipid mediators, regulate pro-inflammatory and resolution pathways, playing significant anti-inflammatory and neurological roles, which in turn may be beneficial in alleviating the symptomatology of migraine. Omega-3 PUFAs impact various neurobiological pathways and have demonstrated a lack of major adverse events, underscoring their multifaceted approach and safety in migraine management. Although not all omega-3 PUFAs trials have shown beneficial in reducing the symptomatology of migraine, further research is needed to fully establish their clinical efficacy and understand the precise molecular mechanisms underlying the effects of omega-3 PUFAs and PUFA-derived lipid mediators, SPMs on migraine pathophysiology and progression. This review highlights their potential in modulating brain functions, such as neuroimmunological effects, and suggests their promise as candidates for effective migraine prophylaxis.

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“…The discovery of these genus SPMs has provided proof that the resolution phase is orchestrated by local mediators and their biosynthesis from n-3 precursors eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [ 8 ]. The role of SPMs, including resolvins, protectins, and their forms that are synthesised after aspirin intervention, as well as the maresins, has been discussed by a significant number of authors in the literature, with particular reference to neuroinflammation and central neurological disorders (see review [ 9 ]). It is interesting to note that multiple SPMs frequently activate the same receptor and that a single SPM can work by activating multiple receptors [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Uncovering the Power of GPR18 Signalling: How RvD2 and Other Ligands Could Have the Potential to Modulate and Resolve Inflammation in Various Health Disorders

Honkisz-Orzechowska,

Łażewska,

Baran

et al. 2024

Molecules

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The resolution of inflammation is the primary domain of specialised pro-resolving mediators (SPMs), which include resolvins, protectins, and their forms synthesised under the influence of aspirin and the maresins. The role of these SPMs has been discussed by many authors in the literature, with particular reference to neuroinflammation and significant neurological disorders. This review discusses the role of G protein-coupled receptor 18 (GPR18), resolvin D2 (RvD2) activity, and the GPR18-RvD2 signalling axis, as well as the role of small molecule ligands of GPR18 in inflammation in various health disorders (brain injuries, neuropathic pain, neurodegenerative/cardiometabolic/cardiovascular/gastrointestinal diseases, peritonitis, periodontitis, asthma and lung inflammation, Duchenne muscular dystrophy, SARS-CoV-2-induced inflammation, and placenta disorders. The idea of biological intervention through modulating GPR18 signalling is attracting growing attention because of its great therapeutic potential. With this paper, we aimed to present a comprehensive review of the most recent literature, perform a constructive view of data, and point out research gaps.

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Specialized Pro-Resolving Mediators in Neuroinflammation: Overview of Studies and Perspectives of Clinical Applications

Cited by 18 publications

References 110 publications

Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis

Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis

Neuroimmunological effects of omega-3 fatty acids on migraine: a review

Uncovering the Power of GPR18 Signalling: How RvD2 and Other Ligands Could Have the Potential to Modulate and Resolve Inflammation in Various Health Disorders

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