Platelets Contribute to the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Abstract

Rationale Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined. Objective Here we addressed the role of platelets in mediating CNS inflammation in EAE. Results We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control non-diseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression upon platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ib alpha (GPIbα) promotes both platelet adhesion as well as inflammatory actions of platelets, and, targeting of GPIbα attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa) also reduced EAE severity in mice. Conclusions Thus, platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.

Platelets induce apoptosis via membrane-bound FasL

“…[6][7][8] PLT dysregulation contributes significantly to initiation or progression of pathologies. 5,9,10 Accordingly, the pathogenetic role of PLTs has been demonstrated in diseases of high socio-economic relevance including atherosclerosis or ischemic stroke, 11,12 but also in unexpected disease settings such as multiple sclerosis 13 or rheumatoid arthritis. 14 In the latter, PLTs amplify inflammation via collagen-dependent microparticle production, 14 whereas in the former, PLT activation contributes to neuronal tissue damage by recruitment and activation of inflammatory cells.…”

Platelets: bridging hemostasis, inflammation, and immunity

“…In this way, platelets can amplify neutrophil recruitment signals or can serve to recruit neutrophils to areas of the vasculature devoid of, or with low levels of, classic neutrophil adhesion molecules. This ability of platelets to mediate adhesion of neutrophils has been clearly demonstrated in a mouse model of autoimmune encephalomyelitis in which blockade of plateletendothelium interactions was able to dramatically reduce neutrophil adherence within the brain microvasculature [20].…”

“…Furthermore, increasing evidence indicates that the excessive production of NETs and the deposition of their associated cytotoxic molecules on endothelium can lead to cellular death and tissue damage [17,23]. Finally, studies showing a role for platelets in pathogenesis in models of multiple sclerosis, rheumatoid arthritis, and other inflammatory diseases are emerging [6,20].…”

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

“…Platelets are key mediators in the initiation and maintenance of a chronic proinflammatory and prothrombotic milieu by direct interactions with inflammatory cells and secretion of autocrine and paracrine effector molecules. Beyond this, recent experimental studies document that platelets are critically involved in autoimmune diseases and innate immunity (188)(189)(190). Data from the animal and human model systems suggest that modification of platelet function may also modulate expression of established inflammatory mediators like CD40L, CD62P, CRP, and TNF-α, and the formation of PLA.…”