Download role of the platelets in inflammationand immunity

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.