Platelets Provide a Bounty of Potential Targets for Therapy in Multiple Sclerosis

Steinman, Lawrence

doi:10.1161/circresaha.112.269050

Cited by 16 publications

(16 citation statements)

References 10 publications

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“…Interestingly, damage to the bulbospinal serotonergic fibers occurs in patients with MS reflecting reduced levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, in the CSF of patients with MS ( Deckx, Lee, Berneman, & Cools, 2013 ). Thus, as patients with MS have lower levels of brain serotonin, the role of platelet serotonin at damage sites in CNS becomes even more crucial and direct modulation of platelets and platelet derived serotonin could provide a bounty of potential targets for treatment of MS ( Steinman, 2012 ). NaHS previously shown to inhibit platelet aggregation and adhesiveness (Gao et al, 2014) could be an appropriate choice to counteract MS condition.…”

Section: Discussionmentioning

confidence: 99%

Pathophysiological Concepts in Multiple Sclerosis and the Therapeutic Effects of Hydrogen Sulfide

Talaei

2016

BCN

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Introduction:Multiple sclerosis (MS) is generally known as a manageable but not yet curable autoimmune disease affecting central nervous system. A potential therapeutic approach should possess several properties: Prevent immune system from damaging the brain and spinal cord, promote differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes to produce myelin, prevent the formation of fibronectin aggregates by astrocytes to inhibit scar formation, and enhance function of healthy endothelial cells (ECs).Methods:To determine if an increase in sulfur contents through H2S, a potent antioxidant known to induce protective autophagy in cells, could provide the above desired outcomes, peripheral blood mononuclear cells (PBMNCs), OCPs, astrocytes, and ECs were treated with NaHS (50 μM) in vitro.Results:Transmigration assay using EC monolayer showed that serotonin increased migration of PBMNC while pretreatment of EC with NaHS inhibited the migration induced by serotonin treatment. NaHS upregulated proteins involved in immune system response and downregulated PBMNCs- and EC-related adhesion molecules (LFA-1 and VCAM-1). Furthermore, it had a cell expansion inducing effect, altering EC morphology. The effects of NaHS on OPCs and astrocytes were studied compared to mTOR inhibitor rapamycin. In NaHS treated astrocytes the induced fibronectin production was partially inhibited while rapamycin almost fully inhibited fibronectin production. NaHS slowed but did not inhibit the differentiation of OCPs or the production of myelin compared to rapamycin.Conclusion:The in vitro results point to the potential therapeutic application of hydrogen sulfide releasing molecules or health-promoting sulfur compounds in MS.

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Section: Discussionmentioning

confidence: 99%

Pathophysiological Concepts in Multiple Sclerosis and the Therapeutic Effects of Hydrogen Sulfide

Talaei

2016

BCN

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“…Furthermore, platelets and platelet-associated molecules have been tested as targets for imaging tools in vascular inflammation [100]. Thereby, platelets and their activation status merit consideration as a tool and biomarker in immune-mediated disease prediction [35] and also as targets for therapy of (neuro-)inflammation [49,101]. A recent report has implicated platelets as effectors of tissue remodeling processes such as apoptosis after brain damage using a model of transient ischemia [102].…”

Section: Future Prospects/concluding Remarksmentioning

confidence: 99%

The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

Pankratz

Bittner

Kehrel

et al. 2016

IJMS

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Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The identification of novel molecular mechanisms linking inflammation and to platelets has highlighted them as new targets for therapeutic interventions. In particular, genetic and pharmacological studies have identified an important role for platelets in neuroinflammation. This review summarizes the main molecular links between platelets and inflammation, focusing on immune regulatory factors, receptors, cellular targets and signaling pathways by which they can amplify inflammatory reactions and that make them potential therapeutic targets.

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“…These drugs are only partially effective and many have side effects 18 . There are no treatments for MS that target platelets 19 ; however, we recently showed that FDA-approved drug Copaxone affected platelet activation 20 . Thus, the study of interactions of platelets with CD4 T cells has the potential to identify new diagnostic and therapeutic targets for MS.…”

Section: Introductionmentioning

confidence: 99%

Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation

Starossom

Veremeyko

Yung

et al. 2015

Circulation Research

110

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Rationale Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases such as multiples sclerosis (MS) is unknown. Autoimmune CD4 T cells have been the main focus of studies of MS, although the factors that regulate T cell differentiation towards pathogenic Th1/Th17 phenotypes are not completely understood. Objectives We investigated the role of platelets in the modulation of CD4 T cell functions in MS patients and in mice with experimental autoimmune encephalitis (EAE), an animal model for MS. Methods and Results We found that early in MS and EAE platelets degranulated and produced a number of soluble factors serotonin (5HT), PF4 and PAF, which specifically stimulated differentiation of T cells towards pathogenic Th1, Th17 and IFN-γ/IL-17-producing CD4 T cells. At the later stages of MS and EAE platelets became exhausted in their ability to produce proinflammatory factors and stimulate CD4 T cells, but substantially increased their ability to form aggregates with CD4 T cells. Formation of platelet-CD4 T cell aggregates involved interaction of CD62P on activated platelets with adhesion molecule CD166 on activated CD4 T cells, contributing to downmodulation of CD4 T cell activation, proliferation and production of IFN-γ. Blocking of formation of platelet-CD4 T cell aggregates during progression of EAE substantially enhanced proliferation of CD4 T cell in the CNS and the periphery leading to exacerbation of the disease. Conclusion Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of CNS autoimmune inflammation.

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Platelets Provide a Bounty of Potential Targets for Therapy in Multiple Sclerosis

Cited by 16 publications

References 10 publications

Pathophysiological Concepts in Multiple Sclerosis and the Therapeutic Effects of Hydrogen Sulfide

Pathophysiological Concepts in Multiple Sclerosis and the Therapeutic Effects of Hydrogen Sulfide

The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation

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