Platelets and vascular inflammation of the brain

Summary

There is emerging evidence that platelets have an important role in inflammation beyond their involvement in hemostasis. Platelets can contribute to inflammatory reactions via crosstalk both with immune cells and endothelial cells. Inflamed vessels are characterized by the presence of activated endothelial cells. These activated endothelial cells upregulate receptors necessary for leukocyte recruitment, but also for the adhesion of platelets. Subsequently, immune cells can bind to platelets through adhesion receptors presented on the platelet surface, thus supporting leukocyte recruitment to the vessel wall. There are several neurological diseases associated with vascular inflammation including multiple sclerosis (MS) and stroke. Increased markers of platelet activation could be demonstrated in patients suffering from MS compared to healthy individuals. Reports from murine models indicate that platelets may be of importance for disease progression and severity by mediating leukocyte recruitment as one potential underlying mechanism. Blocking platelet function disease severity was considerably ameliorated. Moreover, processes of tissue remodelling may be influenced by platelet derived mediators. Whether a role of platelets for vascular inflammation can be extrapolated to further neurological diseases will have to be investigated in further in depth experimental and clinical trials.

Conclusion

Platelets and platelet associated mechanisms may offer novel starting points to understand neurovascular diseases from a different point of view and to develop novel approaches to access the disease.

Zusammenfassung

Neben ihrer Rolle in der Hämostase sind Thrombozyten auch an Entzündungsvorgängen beteiligt. Thrombozyten können sowohl durch Interaktionen mit Immunzellen als auch mit Endothelzellen zu Entzündungsreaktionen beitragen. Vaskuläre Inflammation ist gekennzeichnet durch aktiviertes Endothel. Diese aktivierten Endothelzellen sorgen dafür, dass Rezeptoren hochreguliert werden, die für die Rekrutierung von Leukozyten, aber auch für die Adhäsion von Thrombozyten notwendig sind. In der Folge können Immunzellen mittels Adhäsionsrezeptoren, die auf der Oberfläche der Thrombozyten präsentiert werden, an Thrombozyten binden, wodurch die Rekrutierung von Leukozyten an die Gefäßwand vermittelt wird. Im zentralen Nervensystem gibt es mehrere Erkrankungen wie die Multiple Sklerose (MS) oder der Schlaganfall, die mit vaskulärer Inflammation assoziiert sind. Bei Patienten mit MS konnten erhöhte Marker für Plättchenaktivierung im Vergleich zu Gesunden nachgewiesen werden. Erkenntnisse aus Mausmodellen deuten zudem darauf hin, dass Thrombozyten bedeutsam für die Krankheitsprogression und Krankheitsausprägung sein können, zum Beispiel durch die Vermittlung von Leukozytenrekrutierung in die inflammatorische Läsion. Unter einer Blockade der Thrombozytenfunktion war eine deutliche Verbesserung der Schwere der Erkrankung sichtbar. Darüber hinaus könnten Prozesse des Gewebe-Remodellings durch Mediatoren aus Thrombozyten beeinflusst werden. Ob eine Beteiligung von Thrombozyten an vaskulärer Inflammation auf weitere neurologische Erkrankungen ausgeweitet werden kann, muss in zukünftigen experimentellen und klinischen Arbeiten untersucht werden.

Schlussfolgerung

Thrombozyten bzw. Thrombozyten-assoziierte Mechanismen könnten neue Ausgangspunkte darstellen, um neurovaskuläre Erkrankungen aus einem anderen Blickwinkel zu verstehen oder neue pathophysiologische und therapeutische Ansätze zu definieren.

Keywords

Platelets - inflammation

Schlüsselwörter

Thrombozyten - Entzündung

• References

• 1 Gawaz M, Geisler T. Coronary artery disease: Platelet activity: an obstacle for successful PCI. Nat Rev Cardiol 2009; 06: 391-392.
• 2 Von Hundelshausen P, Schmitt MM. Platelets and their chemokines in atherosclerosis-clinical applications. Front Physiol 2014; 05: 294.
• 3 Van Gils JM, Zwaginga JJ, Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol 2009; 85: 195-204.
• 4 Langer HF, Chavakis T. Platelets and neurovascular inflammation. Thromb Haemost 2013; 110: 888-893.
• 5 Stoll G, Kleinschnitz C, Nieswandt B. Combating innate inflammation: a new paradigm for acute treatment of stroke?. Ann NY Acad Sci 2010; 1207: 149-154.
• 6 Kraft P. et al. Acute ischemic stroke. New approaches to antithrombotic treatment. Nervenarzt 2012; 83: 435-449.
• 7 Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008; 112: 3555-3562.
• 8 Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic stroke: a thrombo-inflammatory disease?. J Physiol 2011; 589: 4115-4123.
• 9 Steinman L. Platelets provide a bounty of potential targets for therapy in multiple sclerosis. Circ Res 2012; 110: 1157-1158.
• 10 Gruner S. et al. Multiple integrin-ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo. Blood 2003; 102: 4021-4027.
• 11 Inoue O. et al. Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J Cell Biol 2003; 160: 769-780.
• 12 Gawaz M. et al. Vitronectin receptor (alpha(v)beta3) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction. Circulation 1997; 96: 1809-1818.
• 13 Weber C, Springer TA. Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to alphaIIbbeta3 and stimulated by platelet-activating factor. J Clin Invest 1997; 100: 2085-2093.
• 14 Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med 1998; 187: 329-339.
• 15 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-297.
• 16 Massberg S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896.
• 17 Massberg S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 2003; 197: 41-49.
• 18 Frenette PS. et al. P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J Exp Med 2000; 191: 1413-1422.
• 19 Dole S. et al. PSGL-1 regulates platelet P-selectinmediated endothelial activation and shedding of P-selectin from activated platelets. Thromb Haemost 2007; 98: 806-812.
• 20 Weber KS, Alon R, Klickstein LB. Sialylation of ICAM-2 on platelets impairs adhesion of leukocytes via LFA-1 and DC-SIGN. Inflammation 2004; 28: 177-188.
• 21 Schulz C. et al. Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: a critical role for P-selectin expressed on activated platelets. Circulation 2007; 116: 764-773.
• 22 Langer HF. et al. Platelets recruit human dendritic cells via Mac-1/JAM-C interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc Biol 2007; 27: 1463-1470.
• 23 Karshovska E. et al. Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice. Circ Res 2015; 116: 587-599.
• 24 Feigin VL. et al. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003; 02: 43-53.
• 25 Yilmaz A. et al. Accumulation of immune cells and high expression of chemokines/chemokine receptors in the upstream shoulder of atherosclerotic carotid plaques. Exp Mol Pathol 2007; 82: 245-255.
• 26 Kleinschnitz C. et al. Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 2007; 115: 2323-2330.
• 27 Massberg S. et al. Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb. Circulation 2005; 112: 1180-1188.
• 28 Kleinschnitz C. et al. Deficiency of von Willebrand factor protects mice from ischemic stroke. Blood 2009; 113: 3600-3603.
• 29 Bongers TN. et al. High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability. Stroke 2006; 37: 2672-2677.
• 30 Weyrich AS, Zimmerman GA. Platelets: signaling cells in the immune continuum. Trends Immunol 2004; 25: 489-95.
• 31 Thornton P. et al. Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood 2010; 115: 3632-3639.
• 32 Walsh PN. Platelet coagulation-protein interactions. Semin Thromb Hemost 2004; 30: 461-471.
• 33 Kleinschnitz C. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 2006; 203: 513-518.
• 34 Kuijpers MJ. et al. Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arterioscler Thromb Vasc Biol 2014; 34: 1674-1680.
• 35 Bjorkqvist J, Jamsa A, Renne T. Plasma kallikrein: the bradykinin-producing enzyme. Thromb Haemost 2013; 110: 399-407.
• 36 Heydenreich N. et al. C1-inhibitor protects from brain ischemia-reperfusion injury by combined antiinflammatory and antithrombotic mechanisms. Stroke 2012; 43: 2457-2467.
• 37 Muller F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
• 38 Langhauser F. et al. Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation. Blood 2012; 120: 4082-4092.
• 39 Göb E. et al. Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation. Ann Neurol 2015; 77: 784-803.
• 40 Malgorzata P. et al. Platelet reactivity in patients with stroke and hyperlipidemia, GPIbalpha assessment. Clin Appl Thromb Hemost. 2014 doi: 10.1177/1076029614543823.
• 41 Salomon O. et al. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008; 111: 4113-4117.
• 42 WHO. Neurological Disorders – A Public Health Approach. 2006 (cited 29.10.2014) www.who.int/mental_health/neurology/chapter_3_a_neuro_disorders_public_h_challenges.pdf?ua=1
• 43 Ffrench-Constant C. Pathogenesis of multiple sclerosis. Lancet 1994; 343: 271-275.
• 44 Steinman L. et al. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci 2002; 25: 491-505.
• 45 Kihara Y. et al. Dual phase regulation of experimental allergic encephalomyelitis by platelet-activating factor. J Exp Med 2005; 202: 853-863.
• 46 Callea L. et al. Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 1999; 94: 212-221.
• 47 Langer HF. et al. Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 2012; 110: 1202-1210.
• 48 Lock C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002; 08: 500-508.
• 49 Kniewallner KM. et al. Platelets in the Alzheimer’s disease brain: do they play a role in cerebral amyloid angiopathy?. Curr Neurovasc Res 2015; 12: 4-14.
• 50 Doring A. et al. E-and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice. J Immunol 2007; 179: 8470-8479.
• 51 Han MH. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008; 451: 1076-1081.
• 52 Habets KL, Huizinga TW, Toes RE. Platelets and autoimmunity. Eur J Clin Invest 2013; 43: 746-757.
• 53 Duerschmied D. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013; 121: 1008-1015.
• 54 Mostert JP. et al. Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a doubleblind, placebo-controlled, exploratory study. J Neurol Neurosurg Psychiatry 2008; 79: 1027-1031.
• 55 Sheremata WA. et al. Evidence of platelet activation in multiple sclerosis. J Neuroinflammation 2008; 05: 27.
• 56 Saenz-Cuesta M. et al. Circulating microparticles reflect treatment effects and clinical status in multiple sclerosis. Biomark Med 2014; 08: 653-661.
• 57 Starossom SC. et al. Glatiramer acetate (copaxone) modulates platelet activation and inhibits thrombin-induced calcium influx: possible role of copaxone in targeting platelets during autoimmune neuroinflammation. PLoS One 2014; 09: e96256.