ROLE OF THE PLATELETS IN INFLAMMATION AND IMMUNITY

Authors: Radu Andrei Tomai Cluj Antoine Joubert Nantes

Supervisor: Zsófia Mezei-Leprán, MD, PhD associate professzor

University of Szeged, Faculty of Medicine Department of Pathophysiology

Introduction

Production :In the bone marrowFrom megakaryocytes

Granules : Alpha :

adhesion molecules mitogenic factors inflammatory mediators growth factors vWF fibrinogen

Dense: ATP ADP serotonin calcium ion

Primary haemostasis, three steps: Adhesion Activation Aggregation

https://usmle287.files.wordpress.com/2012/09/20120930-021358.jpg

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.pngIHD: 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/670e602e8c1165ca244d596148c302e477d66213fca2d3c2fd58156f8a900d54/pic003.jpg

Second line of defense

Innate immunity

Nonspecific

PRR recognize PAMP TLR,NLR,RLR

Phagocytes

Complement system

Inflammation

Body lines of defensehttp://people.eku.edu/ritchisong/301im

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Body lines of defense

Third line 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/Im

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Platelets’ involvement in the lines of defense

Second line of defenseSensing the environment: Membrane receptors TLR:

Membrane: TLR1, 2, 6, 4, 5 Intracellular: TLR9, 3, 7

Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-376.

Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335-376.

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

Platelets’ involvement in the lines of defenseSecond line of defense

Second line of defensePlatelets’ involvement in the lines of defense

SIGLEC proteins

Modulate immune response

Cis bound to sialic acids ↓ immune response

Sialidase/sialyated glycans -> trans bond ↑immune response

Siglec-7 negative regulation of inflammation

Front Immunol. 2015;6:83. 10.3389/fimmu.2015.00083. eCollection 2015.

Platelets’ involvement in the lines of defenseSecond line of defense

Platelets-leukocytes interactions

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

Semple JW, Italiano JE Jr, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264-274.

Platelets’ involvement in the lines of defenseSecond 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.jpg

Platelets’ involvement in the lines of defenseThird line of defensePlatelets: 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

The effect of platelets on adaptive immune responses during activation, proliferation, and migrationElzey, 2011

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 drugsLow dose aspirin:

Inhibits COX1 of platelets – not of endothelial cells Reduces TXA2 synthesis

Acetylates COX2 Produces aspirin triggered lipoxin

Anti-inflammatory Resolution of tissue structure and function Produced by transcellular synthesis

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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.