ROLE OF THE PLATELETS IN INFLAMMATION AND IMMUNITY

ROLE OF THE PLATELETS IN INFLAMMATION AND IMMUNITY Authors: Radu Andrei Tomai Cluj Antoine Joubert Nantes Supervisor: Zsófia Mezei-Leprán, MD, Ph. D associate professzor University of Szeged, Faculty of Medicine Department of Pathophysiology

Introduction Production : In the bone marrow From megakaryocytes Granules : Ø Alpha : Ø adhesion molecules Ø mitogenic factors Ø inflammatory mediators Ø growth factors Ø v. WF Ø fibrinogen Ø Dense: Ø ATP Ø ADP Ø serotonin Ø calcium ion https: //usmle 287. files. wordpress. com/2012/09/20120930 -021358. jpg Primary haemostasis, three steps: Ø Adhesion Ø Activation Ø Aggregation

Atherosclerosis Ø Chronic innate immunity Ø Chronic adaptive immunity Ø 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 Ø Nonspecific defense –innate Ø Physical aspect Ø Barriers, mucus Ø Chemical aspect Ø PH Ø Cellular aspect http: //8 c 4625. medialib. glogster. com/media/6 70 e 602 e 8 c 1165 ca 244 d 596148 c 302 e 477 d 662 13 fca 2 d 3 c 2 fd 58156 f 8 a 900 d 54/pic 003. jpg

Body lines of defense Ø Innate immunity Ø Nonspecific Ø PRR recognize PAMP Ø TLR, NLR, RLR Ø Phagocytes Ø Complement system Ø Inflammation http: //people. eku. edu/ritchisong/301 images/Immunity_Innate. Adaptive. jpg Second line of defense

Body lines of defense Ø Ø Adaptive immunity Long lasting memory Specific Efficient Ø Humoral immunity → B lymphocytes : Igs Ø Cellular immunity → T lymphocytes Ø T CD 8+ cytotoxic Ø T CD 4+ helper http: //people. eku. edu/ritchisong/301 images/Immunity_Innate. Adaptive. jpg Third line of defense

Platelets’ involvement in the lines of defense Second line of defense Sensing the environment: Membrane receptors Ø TLR: Ø Membrane: Ø Intracellular: TLR 1, 2, 6, 4, 5 TLR 9, 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 Ø TLR 4: Ø ↑expression in activated platelets Ø Binds LPS with help of MD 2, LBP, DC 14 Ø TF production Ø Cytokine synthesis regulation Ø TLR 2 Ø Binds lipopeptides, lipoteichoic acids, peptidoglycans Ø TLR 2 -TLR 1 dimer : tryacilated lipopeptides Ø TLR 2 -TLR 6 dimer: diacylated lipopeptides Ø TLR 9 Ø Binds unmethylated Cp. G motifs, oxidative stress products Ø 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 Ø Modulate immune response Ø Cis bound to sialic acids Ø ↓ immune response Front Immunol. 2015; 6: 83. 10. 3389/fimmu. 2015. 00083. e. Collection 2015. Ø Sialidase/sialyated glycans -> trans bond Ø ↑immune response Ø 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. Ø Adhesive mechanisms Ø P-selectin –PSGL-1 →WBC transmigration Ø GPIbα -Mac-1 integrin → inflammation and thrombosis Ø ICAM-2 - Mac-1 → adhesion and migration Ø Soluble mechanisms Ø Release of α-granules Ø CD 40 L Ø NET formation – CXCL 4 -CCL 5, TLR 4

Platelets’ involvement in the lines of defense Second line of defense Platelet- complement system interaction Ø Release of kinases → phosphorylate C 3 and C 3 b Ø PAF→ ↑ phagocytosis of opsonized RBC Ø Complement can activate platelets Ø Platelets in inflammation Ø P-selectin facilitates leukocyte mobility http: //www. cell. com/cms/attachment/586910/4460670/gr 1. j pg

Platelets’ involvement in the lines of defense Third line of defense Platelets: CD 40 receptor on membrane Ø Massive production of CD 40 L : Ø →the majority of circulating CD 40 L Ø co-receptor for lymphocytes maturation Ø Absence →deleterious for the immune system Ø Effects: Ø maturation of B cells even with few T CD 4+ Ø production of T lymphocytes Ø ↑ T CD 8+ cytotoxic function Communication with cells Ø Platelet→CXCL 4/CCL 5→ T cell maturation Ø Platelet→serotonin→ prevents T CD 8+ 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 Ø Regular exercise ↓ platelets' aggregation Ø Not the case for acute exercise Ø ↓ prevalence of cardiovascular disease in Mediterranean region Ø Polyphenols Ø antioxidants Ø inhibit NADPH oxydase which produces O 2 -. Ø O 2 - destroys NO to limit its antiaggregating effect.

ANTIPLATELET THERAPY EFFECT ON THE DISORDERS Ø Action depends on patient : Ø Clopidogrel → liver → active metabolite Ø Liver disfunction influences quality of treatment Ø Side-effects: Ø hemorrhage Ø nausea Ø abdominal pain Ø Nowadays → combined therapies: Ø broader and more efficient. Ø associates an anticoagulant with dual platelet antitherapy http: //pharmacologycorner. com/antiplatelet-agents/ Ø Antiplatelet →↓ thrombi formation →↓bacteria proliferation in thrombi mileu→| platelet activation → WBC recruitment

Application of drugs ØLow dose aspirin: Ø Inhibits COX 1 of platelets – not of endothelial cells Ø Reduces TXA 2 synthesis Ø Produces aspirin triggered lipoxin Ø Anti-inflammatory Ø Resolution of tissue structure and function Ø Produced by transcellular synthesis http: //www. pnas. org/content/101/42/15178/F 1. large. jpg Ø Acetylates COX 2

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.