Platelets Play a role in the mechanism of Innate Immunity.
The interaction of platelets with bacteria depends on the nature and concentration of bacteria, the time of interaction, and involves many mechanisms. The role of platelets in dealing with pathogenic bacteria is by cooperating with neutrophils to form a bacterial entrapment net involving Toll-like receptor 4 (TLR4) which can detect LPS and induce platelet binding to immobilize (bind) neutrophils. Indirect interactions such as through binding of plasma proteins, including fibrinogen, von Willebrand factor, complement or IgG, which bridge the pathogen and platelets or through interactions with bacterial toxins. Interaction with pathogens can lead to platelet adhesion or their activation, aggregation and release of platelet mediators. The mechanism of pathogen clearance by platelets may be direct, through the release of various antimicrobial peptides and indirectly through the release of platelet-derived mediators that coordinate chemotaxis and immune cell activation. Infection is generally associated with tissue injury. Injured cells produce alarm-like mediators that trigger inflammation. Mediators produced by cell damage such as complement activation products and histones can activate platelets. However, platelets also contribute to the adaptive immune response to infection
(A) Platelet TLR allows activated platelets to bind and capture bacteria. Furthermore, platelets can directly kill bacteria by producing thrombocidin or by gathering around bacteria and “trapping” them for removal by phagocytes. (B) Platelets can also heterotifically interact with various cells, including leukocytes. Activated platelets promote neutrophil binding and activation through the expression of selectins, CD154 (also known as CD40L), and inflammatory cytokines and chemokines. (C) Activated platelets can increase monocyte and dendritic cell (DC) activation, particularly through CD40-CD154 interaction. This causes an increase in antigen presentation on T cells and enhances the adaptive immune response. MHC, major histocompatibility complex; TCR, T-cell receptor.12
Through signal transduction TLR2 induces the expression of P-selectin (CD62P) and GPIIb/IIIa (integrin IIβ3) on the platelet surface. This molecule facilitates the interaction of platelets with neutrophils resulting in phagocytosis of pathogenic microbes. Clark et al, reported that TLR4 induces platelet-neutrophil binding via NETs (Neutrophil Extracellular Traps), tissue neutrophil extracellular traps, as pathogen traps. After the bacteria are entangled, it will facilitate the process of phagocytosis of these bacteria by neutrophils.
Platelets circulate closer to the vessel wall and sense endothelium disruption. In sepsis, many cellular factors activate the endothelium. Activated/injured endothelium is the main driver of platelet activation. Signals generated by infection, inflammation and coagulation can also activate platelets in sepsis. Platelet activation contributes to triggering various pro-inflammatory and pro-coagulant pathways with potentially damaging consequences on homoeostasis and endothelium integrity. Unreduced platelet activation in sepsis may play an important role in the complex global scenario leading to endothelial barrier disruption and microcirculatory failure, the main cause of organ dysfunction in sepsis.
This mechanism of NET formation will only occur in extreme conditions such as in severe sepsis and TLR4 from platelets serves as an important triggering tool. With the use of antibiotics, reducing the NET formation mechanism to trap and kill bacteria, inhibition of this mechanism can reduce tissue damage
Platelets Affect Lymphocytes as Body Defense.
Platelets have the potential to activate adaptive immunity. Elzey et al demonstrated that platelets facilitate T/B cell interactions via CD40 leading to antibody production. CD40 induces cytokines, chemokines, and lipid mediators through the activation of CD+40 cells. These cytokines potentiate the function of neutrophils in defense against Gram-positive and Gram-negative bacteria. Henn et al, found that platelets release CD40L which regulates endothelial cell responses in vascular mediation as a body defense. 6,7,8
upon activation, platelets release their -granules, which contain high amounts of CXCL4, which enhances the regulation of coagulation and leukocyte recruitment. In addition, CXCL4 reduced HIV infection but also increased liver fibrosis. CCL5, another granule-derived chemokine, also reduces HIV infection and enhances Th1 lymphocyte responses in HCV infection and serves as a survival signal for macrophages in influenza infection. Platelets release PMP and -defensin from their -granules, which mediate viral neutralization. They protect splenocytes from necrosis in LCMV infection. Platelet solid granules contain 5-HT, which allows liver regeneration but also HBV and HCV infection. Platelet activation leads to the expression and release of CD154 and CD62P, which allows direct interaction between platelets and leukocytes. The interaction of platelets with B lymphocytes increases the formation of germinal centers and the production of antiviral IgG. Platelets trigger T-lymphocyte differentiation and cytotoxicity as well as monocyte survival and differentiation. In neutrophils, platelet adhesion stimulates ROS production and enhances phagocytosis. The interaction of platelets with dendritic cells increases their maturation and facilitates antigen presentation. Finally, platelet activation results in further platelet interaction and activation, which triggers platelet aggregation and amplifies the process described above. CCL5, chemokine (C–C motif) ligand 5; CXCL4, C–X–C chemokine ligand 4, GP, glycoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IgG, immunoglobulin G; LCMV, lymphocytic choriomeningitis; PMPs, Platelet antimicrobial peptides; PSGL-1, P-selectin (CD62P) glycoprotein ligand-1; sCD154, soluble CD154/CD40 ligand; Th1, T-helper lymphocyte type 1; 5-HT, serotonin.14
Platelets Play a Role in Tissue Remodeling.
Platelets also play a role in tissue remodeling, wound healing, for example by releasing growth factors PDGF and TGF-b which regenerate the extracellular matrix in tissue repair. In addition to other growth factors released from platelets such as VEGF, FGF, IGF-1, P-degF, these factors play a role in tissue repair which is an integral part of wound healing.6
Clinical Applications The Role of Platelets in Immunology
Reactive (secondary) thrombocytosis, platelet count >500 x 109 /l but < 1000 x 109 /l. Reactive thrombocytosis is common in premature infants and after infection, especially meningitis. Acute or chronic infection is a predisposing factor for reactive thrombocytosis. In reactive thrombocytosis there is an increase in the release of cytokines in response to infection, inflammation, vasculitis, tissue trauma and other factors: thrombopoietin (TPO) and interleukin 6, a cytokine primary for platelet formation, will increase as an initial response and stimulate increased production of platelets.
Platelets have receptors on the surface and cytoplasmic granules that act as antimicrobials, namely as microbicidal proteins
Platelets interact directly with pathogenic microbes by releasing thrombocidin & indirectly with the mechanism of innate immunity through activation of neutrophils and monocytes and adaptive immunity through T lymphocytes, B lymphocytes and dedritic cells.
Platelets play a role in tissue remodeling.
The clinical application of the role of platelets in immunology is reactive (secondary) thrombocytosis in response to infection.
- Hoffbrand, A.V dan Mehta, A 2008.At a Glance Hematologi. edisi 2 Erlangga Medical Series.
- Campbell, Neil A. (2008). Biology (edisi ke-8th). London: Pearson Education. hlm. 912
- Hoffbrand, A.V dan Moss, P.A.H., 2013. Trombosit, Koagulasi Darah, dan Hemostasis (Kapita Selekta Hematologi edisi 6). Penerbit Buku Kedokteran. EGC.
- Bain, B.J. 2014. Trombosit, Koagulasi dan Hemostasis (haematology : A Core Curriculum) . Penerbit Buku Kedokteran.EGC.
- Harrison, Paul. Trombosit function available at http:// www. sciencedirect. com/ science/article.
- Yeaman, M.R dan Bayer, A.S.2013. Antimicrobial Host Defense. Chapter 37 (hal ;812-846). Elsevier.
- Yeaman, Michael R. Bacterial–trombosit interactions: virulence meets host defense. March 2010. Future Microbiology. Vol. 5, No. 3, Pages 471-506
- Trier, Darin A. , Gank, Kimberly D. , Michael R. Yeaman., Trombosit Antistaphylococcal Responses Occur through P2X1 and P2Y12 Receptor-Induced Activation and Kinocidin Release.Published ahead of print 29 September 2008, doi: 1128/IAI.00935-08 Infect. Immun. December 2008 vol. 76 .
- Carsten D., Paul K. Platelets and infection. Semin Immunol (2016),http://dx.doi.org/10.1016/j.smim.2016.10.005
Antoine D., et al. Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critical ill patients?.Dewitte et al. Ann. Intensive Care (2017) 7:115