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ROLE OF THE PLATELETS IN INFLAMMATION AND IMMUNITY Authors: Radu Andrei Tomai Antoine Joubert Cluj Nantes Supervisor: Zsófia Mezei-Leprán, MD, PhD associate professzor University of Szeged, Faculty of Medicine Department of Pathophysiology Introduction Production : In the bone marrow From megakaryocytes Granules : Alpha : adhesion molecules mitogenic factors inflammatory mediators growth factors vWF fibrinogen Dense: ATP ADP serotonin calcium ion https://usmle287.files.wordpress.com/2012/09/20120930-021358.jpg Primary haemostasis, three steps: Adhesion Activation Aggregation Atherosclerosis Chronic innate immunity Chronic adaptive immunity Chronic inflammation Death brats Worldwide 2012 (WHO) Combining IHD, Strokes and HHD. http://baltimorepostexaminer.com/wp-content/uploads/Atherosclerosis-2012.png IHD: ischemic heart disease, HHD: hypertensive heart disease, WHO: World Health Organization Body lines of defense First line of defense Nonspecific defense –innate Physical aspect Barriers, mucus Chemical aspect PH Cellular aspect http://8c4625.medialib.glogster.com/media/6 70e602e8c1165ca244d596148c302e477d662 13fca2d3c2fd58156f8a900d54/pic003.jpg Body lines of defense Innate immunity Nonspecific PRR recognize PAMP TLR,NLR,RLR Phagocytes Complement system Inflammation http://people.eku.edu/ritchisong/301images/Immunity_InnateAdaptive.jpg Second line of defense Body lines of defense Adaptive immunity Long lasting memory Specific Efficient Humoral immunity → B lymphocytes : Igs Cellular immunity → T lymphocytes T CD8+ cytotoxic T CD4+ helper http://people.eku.edu/ritchisong/301images/Immunity_InnateAdaptive.jpg Third line of defense Platelets’ involvement in the lines of defense Second line of defense Sensing the environment: Membrane receptors TLR: Membrane: Intracellular: TLR1, 2, 6, 4, 5 TLR9, 3, 7 Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-376. Platelets’ involvement in the lines of defense Second line of defense TLR4: ↑expression in activated platelets Binds LPS with help of MD2, LBP, DC 14 TF production Cytokine synthesis regulation TLR 2 Binds lipopeptides, lipoteichoic acids, peptidoglycans TLR2-TLR1 dimer : tryacilated lipopeptides TLR2-TLR6 dimer: diacylated lipopeptides TLR9 Binds unmethylated CpG motifs, oxidative stress products Causes degranulation and aggregation Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-376. Platelets’ involvement in the lines of defense Second line of defense SIGLEC proteins Modulate immune response Cis bound to sialic acids ↓ immune response Front Immunol. 2015;6:83. 10.3389/fimmu.2015.00083. eCollection 2015. Sialidase/sialyated glycans -> trans bond ↑immune response Siglec-7 negative regulation of inflammation Platelets’ involvement in the lines of defense Second line of defense Platelets-leukocytes interactions Semple JW, Italiano JE Jr, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264-274. Adhesive mechanisms P-selectin –PSGL-1 →WBC transmigration GPIbα -Mac-1 integrin → inflammation and thrombosis ICAM-2 - Mac-1 → adhesion and migration Soluble mechanisms Release of α-granules CD40L NET formation – CXCL4-CCL5, TLR4 Platelets’ involvement in the lines of defense Second line of defense Platelet- complement system interaction Release of kinases → phosphorylate C3 and C3b PAF→ ↑ phagocytosis of opsonized RBC Complement can activate platelets Platelets in inflammation P-selectin facilitates leukocyte mobility http://www.cell.com/cms/attachment/586910/4460670/gr1.j pg Platelets’ involvement in the lines of defense Third line of defense Platelets: CD40 receptor on membrane Massive production of CD40L : →the majority of circulating CD40L co-receptor for lymphocytes maturation Absence →deleterious for the immune system Effects: maturation of B cells even with few T CD4+ production of T lymphocytes ↑ T CD8+ cytotoxic function Communication with cells Platelet→CXCL4/CCL5→ T cell maturation Platelet→serotonin→ prevents T CD8+ from entering liver Elzey, 2011 The effect of platelets on adaptive immune responses during activation, proliferation, and migration ANTIPLATELET THERAPY EFFECT ON THE DISORDERS Physical exercise and Diet Regular exercise ↓ platelets' aggregation Not the case for acute exercise ↓ prevalence of cardiovascular disease in Mediterranean region Polyphenols antioxidants inhibit NADPH oxydase which produces O2-. O2- destroys NO to limit its antiaggregating effect. ANTIPLATELET THERAPY EFFECT ON THE DISORDERS Action depends on patient : Clopidogrel → liver → active metabolite Liver disfunction influences quality of treatment Side-effects: hemorrhage nausea abdominal pain Nowadays → combined therapies: broader and more efficient. associates an anticoagulant with dual platelet antitherapy http://pharmacologycorner.com/antiplatelet-agents/ Antiplatelet →↓ thrombi formation →↓bacteria proliferation in thrombi mileu→| platelet activation → WBC recruitment Application of drugs Low dose aspirin: Inhibits COX1 of platelets – not of endothelial cells Reduces TXA2 synthesis Produces aspirin triggered lipoxin Anti-inflammatory Resolution of tissue structure and function Produced by transcellular synthesis http://www.pnas.org/content/101/42/15178/F1.large.jpg Acetylates COX2 Summary Platelets play an important role in hemostasis, inflammation and immunity .They are not only passive, as previously thought but also active. Their importance is reflected in their involvement in diseases such as atherosclerosis . The studies have yet only outlined their value. Thank you for your attention. Gratitude to our supervisor Zsófia Mezei-Leprán for advising us and coordinating our activity.