Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function

Abstract

BackgroundCell-derived microparticles are secreted in response to cell damage or dysfunction. Endothelial and platelet dysfunction are thought to contribute to the development of multiple sclerosis (MS). Our aim here is, first, to compare the presence of microparticles of endothelial and platelet origin in plasma from patients with different clinical forms of MS and with clinically isolated syndrome. Second, to investigate the effect of microparticles on endothelial barrier function.ResultsPlatelet-poor plasma from 95 patients (12 with clinically isolated syndrome, 51 relapsing-remitting, 23 secondary progressive, 9 primary progressive) and 49 healthy controls were analyzed for the presence of platelet-derived and endothelium-derived microparticles by flow cytometry. The plasma concentration of platelet-derived and endothelium-derived microparticles increased in all clinical forms of MS and in clinically isolated syndrome versus controls. The response of endothelial barriers to purified microparticles was measured by electric cell-substrate impedance sensing. Microparticles from relapsing-remitting MS patients induced, at equivalent concentrations, a stronger disruption of endothelial barriers than those from healthy donors or from patients with clinically isolated syndrome. MS microparticles acted synergistically with the inflammatory mediator thrombin to disrupt the endothelial barrier function.ConclusionsPlasma microparticles should be considered not only as markers of early stages of MS, but also as pathological factors with the potential to increase endothelial permeability and leukocyte infiltration.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-110) contains supplementary material, which is available to authorized users.

Pulmonary Extracellular Vesicles as Mediators of Local and Systemic Inflammation

“…Several studies have demonstrated the presence of pro-inflammatory EVs at the site of inflammation in RA (Berckmans et al, 2002 ; Song et al, 2005 ), MS (Marcos-Ramiro et al, 2014 ; Sáenz-Cuesta et al, 2014a , b ), and inflammatory bowel disease (IBD; Mitsuhashi et al, 2016 ). MVs (Lindemann et al, 2001 ; MacKenzie et al, 2001 ) and exosomes (Qu et al, 2007 ) from several different cells are transporters of the strongly pro-inflammatory IL-1β, and membrane-bound TNF (mTNF) was found on synovial fibroblast exosomes from RA patients, but not from (non-autoimmune) osteoarthritis patients (Zhang et al, 2006 ).…”

“…MS patients have increased serum levels of platelet MVs, which also correlate with clinical subtype (Sáenz-Cuesta et al, 2014a ). MVs from MS patients disrupted endothelial barriers in vitro (Marcos-Ramiro et al, 2014 ), and EVs have been suggested to contribute to MS by degrading the blood brain barrier, increasing endothelial activation and promoting neural inflammation (Sáenz-Cuesta et al, 2014b ). Fas ligand (FasL)-induced apoptosis is an immune regulatory mechanism, and DC-derived EVs with TNF, FasL and TNF related apoptosis inducing ligand (TRAIL) can activate natural killer cells, and induce tumor cell apoptosis (Munich et al, 2012 ), and could also play a role in systemic inflammation.…”

The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients

“…Platelets are activated in MS and have been implicated in contributing to MS pathogenesis, such as by promoting inflammation [26, 35]. Our results demonstrate, that the activation of platelets from SP MS patients is significantly raised compared to platelets from healthy subjects, and observed differences are directly related to the COX activation.…”

“…Some reports emphasize the importance of platelet activation in MS [35]. Our previous studies also clearly demonstrated that blood platelets are chronically activated in the circulation of SP MS patients [36].…”

Applicability of extracellular vesicles in clinical studies

“…Additionally, we included 25 publications that fulfilled inclusion criteria but were found otherwise. Final analysis was performed on 65 publications (Fig. ).…”