Platelets in Multiple Sclerosis: Early and Central Mediators of Inflammation and Neurodegeneration and Attractive Targets for Molecular Imaging and Site-Directed Therapy

Abstract

Platelets are clearly central to thrombosis and hemostasis. In addition, more recently, evidence has emerged for non-hemostatic roles of platelets including inflammatory and immune reactions/responses. Platelets express immunologically relevant ligands and receptors, demonstrate adhesive interactions with endothelial cells, monocytes and neutrophils, and toll-like receptor (TLR) mediated responses. These properties make platelets central to innate and adaptive immunity and potential candidate key mediators of autoimmune disorders. Multiple sclerosis (MS) is the most common chronic autoimmune central nervous system (CNS) disease. An association between platelets and MS was first indicated by the increased adhesion of platelets to endothelial cells. This was followed by reports identifying structural and functional changes of platelets, their chronic activation in the peripheral blood of MS patients, platelet presence in MS lesions and the more recent revelation that these structural and functional abnormalities are associated with all MS forms and stages. Investigations based on the murine experimental autoimmune encephalomyelitis (EAE) MS model first revealed a contribution to EAE pathogenesis by exacerbation of CNS inflammation and an early role for platelets in EAE development via platelet-neuron and platelet-astrocyte associations, through sialated gangliosides in lipid rafts. Our own studies refined and extended these findings by identifying the critical timing of platelet accumulation in pre-clinical EAE and establishing an initiating and central rather than merely exacerbating role for platelets in disease development. Furthermore, we demonstrated platelet-neuron associations in EAE, coincident with behavioral changes, but preceding the earliest detectable autoreactive T cell accumulation. In combination, these findings establish a new paradigm by asserting that platelets play a neurodegenerative as well as a neuroinflammatory role in MS and therefore, that these two pathological processes are causally linked. This review will discuss the implications of these findings for our understanding of MS, for future applications for imaging toward early detection of MS, and for novel strategies for platelet-targeted treatment of MS.

The Inflammatory Conspiracy in Multiple Sclerosis: A Crossroads of Clues and Insights through Mast Cells, Platelets, Inflammation, Gut Microbiota, Mood Disorders and Stem Cells

“…Circulating IL-1β, IL-6 and IL-8 are not regulated in chronic systemic and silent inflammation and also have receptors on platelets [ 84 ]. Platelets express a variety of immunologically relevant ligands and receptors, adhering with endothelial cells, monocytes and neutrophils and toll-like receptor- (TLR) mediated responses [ 85 ].…”

Hemostasis Components as Therapeutic Targets in Autoimmune Demyelination

“…Primary hemostasis: Rationale to repurpose aspirin as add-on therapy in MS Activated platelets are involved in regulating local inflammatory responses through the interplay between EC and infiltrating leukocyte. 15 The interplay among blood platelets, endothelium, and leukocytosis an underlying mechanism of blood-brain barrier (BBB) dysfunction. 16 Once activated, platelets express CD40L (ligand of CD40, a costimulatory receptor of immune system) and cytokines, such as IL-1ß, that in turn promote EC permeability, recruitment, and attachment on the endothelium of several classes of leukocytes, including neutrophils, monocytes, dendritic cells, and B and T lymphocytes.…”

Potential Roles of Extracellular Vesicles as Biomarkers and a Novel Treatment Approach in Multiple Sclerosis

“…Recently, evidence has emerged suggesting non-haemostatic roles for platelets, including inflammatory and immune responses. An association between platelets and MS was first indicated by the increased adhesion of platelets to endothelial cells in these patients [60]. During this process, platelets release EVs that interact with the underlying endothelium and contribute to the endothelial abnormalities involved in the pathophysiology of MS [61].…”