Platelet Biology

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1		Escribese M. M.	+ 1493 word(s)	1493	2021-12-24 03:01:54	\|
2	format correct	Catherine Yang	Meta information modification	1493	2022-02-14 10:21:40	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms20071730

Platelets are generated from megakaryocytes in a multi-step process called thrombopoiesis regulated by thrombopoietin. Thrombopoietin stimulates its receptor in megakaryocytes to induce the genesis of pro-platelets via a mechanism activated by low platelet counts. Platelet counts in blood are controlled by the rates of production and removal, involving mechanisms of platelet clearance, activation or ageing. Platelets are the most numerous circulating cell type (≈200,000/µL blood in humans) with an immune function.

platelets mediators inflammation allergy

1. Platelets as Coagulation Factors

The traditionally attributed role of platelets is to assure hemostasis. Platelets become rapidly activated and adhere tightly to other platelets and to the wall vessel as soon as damage is found. Briefly, platelets bind to von Willebrand factor (vWF), which forms a bridge with exposed collagen on the injury and glycoprotein Ib (GPIb)/V/IX receptor complex on the platelet membrane. The exposed collagen also binds directly to platelet GPIa/IIa and GPVI receptors to induce platelet activation in a positive feedback loop. Platelets then release mediators such as ADP and serotonin that activate platelet G protein-coupled receptors. This process results in increased levels of cytosolic calcium and activates signaling pathways leading to platelet shape change and activation of integrins, enhancing the adhesion of platelets to the endothelial wall. Furthermore, ADP acts on platelet P2Y1 and P2Y12 G-protein-coupled receptors to sustain platelet activation ^[1]^[2]. Finally, the activation of the GPIIb/IIIa receptor results in the cross-linking of fibrinogen or vWF with their receptors (integrin aIIbβ3) leading to platelet aggregation. This promotes the recruitment of additional platelets to the site of vascular injury allowing the formation of the thrombus ^[3]^[4].

Platelets also participate in biological processes such as vascular integrity, tissue regeneration and angiogenesis, and lymphatic vessel development ^[5]^[6]^[7]^[8]^[9]^[10]^[11]^[12].

2. Platelets as Immune Mediators

Platelets count with several organelles such as mitochondria, lysosomes and peroxisomes, and a plethora of intracellular immune mediators stored in granules and vesicles ^[13]. Moreover, platelets express a high number of membrane receptors and contain cytoplasmic mRNA, which can synthetize a limited number of proteins and miRNA ^[14]^[3]. These receptors and proteins allow them to interact with leukocytes and endothelial cells, both by contact-dependent mechanisms and through secreted immune mediators. Thus, platelets can modulate immune responses at the sites of platelet activation systemically ^[15].

Platelet receptors and the molecules stored in platelet granules govern platelet functions. These molecules are listed in Table 1. There are three types of platelet granules: α-granules, dense granules and lysosomal granules. Additionally, a potential new type of granule termed a T-granule has been described ^[16]. α-granules are the most numerous (50–60 per platelet) and largest (200–400 nm) granules. They contain a large variety of proteins, close to 300, including a diverse range of chemokines, such as CXCL1, platelet factor 4 (PF4), CXCL5, CXCL7, CXCL12, macrophage inflammatory protein (MIP)-1α and regulated on activation normal T expressed and secreted (RANTES) ^[17]. Dense granules are smaller (~150 nm), less abundant (3–8 per platelet) and store small molecules, such as ADP, ATP, inorganic polyphosphate, pyrophosphate, histamine, serotonin, and calcium. Finally, lysosomal granules are sparse and contain proteases and glycosidases ^[4]^[18]. Upon platelet stimulation, granules undergo regulated exocytosis and release their content into the extracellular environment. In addition, molecules found on the inner granule membrane become surface-expressed. Many of these granule-derived molecules are immune mediators.

Table 1. Summary of major platelet-derived inflammatory mediators and membrane receptors.

α-Granules
No.	Molecule	Function
1	PF4 (CXCL4)	Chemokine: Induce leukocyte pro-inflammatory cytokine release in monocyte, neutrophil, and T-cell recruitment; Th differentiation
2	P-selectin	Adhesion molecule: Formation of platelet-leukocyte aggregate; Formation of bridges between leukocytes and endothelium
3	CD40L	TNF superfamily: antigen-presenting cell activation, B-cell responses, endothelial cell activation
4	MIP-1a (CCL3)	Cytokine: neutrophil and eosinophil activation, B-cell immunoglobulin production
5	IL-1β	Cytokine: acute phase response, leukocyte and endothelial activation
6	RANTES (CCL5)	Chemokine: Promotes monocyte, macrophage and T cell recruitment
7	TGF-β	Cytokine: cell proliferation, T-cell differentiation, B-cell and macrophage phenotype regulation
8	PDGF	Growth factor: cell growth and differentiation, monocyte/macrophage differentiation
9	VWF	Platelet adhesion, PMN extravasation
10	CD63	Tetraspanin: transmembrane adaptor protein, leukocyte recruitment
11	SDF-1	Chemokine: T-cell, monocyte, and PMN chemotaxis
12	VEGF	Growth factor: angiogenesis, adhesion molecule expression
13	Ppbp β-thromboglobulin (NAP-2)	Chemokine: neutrophil activation and recruitment, macrophage phagocytic activity
14	Thrombospondins	Apoptosis, endothelial cell inflammation, macrophage-platelet aggregates
15	MMP-2, MMP-9	Protease: extracellular matrix breakdown, platelet-leukocyte aggregate formation
16	Cyclophilin A	Vascular smooth muscle cell growth factor
18	CXCL1, CXCL5, CXCL7, CXCL12	Chemokines
19	Microbial proteins	Cationic proteins: disrupt cell membrane
Dense Granule
No.	Molecule	Immune/Inflammatory Role
1	Serotonin	DC and T-cell functions
2	Glutamate	T-cell trafficking
3	Polyphosphates	Inflammatory response amplification
4	ADP	Platelet, leukocyte, endothelial cell activation
5	Histamine	Increased vessel reactivity and degranulation
6	ATP, phosphate, calcium	Fuel cell and co-factors in thrombosis
7	Eicosanoids	Pro-inflammatory signals
Produced Metabolites
No.	Molecule	Immune/Inflammatory Role
1	Thromboxane	Eicosanoid: T-cell differentiation, monocyte activation
2	Nitric oxide	Reactive oxygen species: anti-inflammatory and antithrombotic
3	GPIbα	Adhesion molecule: binds Mac-1 on leukocytes
4	TXA2	Mediator that enhance platelet activation
5	S1P	Active metabolite which activate platelets and stimulate mitogenesis
6	PAF	Bioactive lipid: induce endothelial migration
7	Chrondroitin sulfate	Metabolite released by platelets after trigger complement activation
8	LPA	Lipid: ligand of G protein-coupled receptors
Membrane Receptors
No.	Molecule	Immune/Inflammatory Role
1	TLR1, TLR2, TLR4, TLR6, TRL8 and TLR9	Receptors that recognize pathogen-associated molecular patterns and mediate inflammatory events
2	CD40, CD40L	Receptor: Mediator of interactions between lymphocytes and antigen presenting cells
3	GPIa, GPIIb/IIIa, GPIc-IIa (VLA-6)	Platelet glycoprotein: adhesion molecules
4	GPVI	Collagen receptor: induces powerful platelet activation
5	P2X1	Receptor is involved in platelet shape change and in activation by collagen
6	P2Y1, P2Y12	G-protein receptors: sustain platelet activation in response to ADP
7	PAR-1, PAR-4	Thrombin activates platelets through proteolytic cleavage of PAR receptors
8	ICAM-2,	Adhesion molecule
10	JAM-A,	Protects from thrombosis by suppressing integrin αIIbβ3

NOTE: ADP, adenosine 5′-diphosphate; CD40L, CD40 ligand; DC, dendritic cell; GPIba, glycoprotein Iba; 5-HT, 5-hydroxytryptamin; IL, interleukin; LPA, lysophosphatydic acid; MIP, macrophage-inflammatory protein; MMP, metalloproteinase; NAP, neutrophil-activating peptide; PAFR, platelet-activating factor receptor; PAR, protease-activated receptors; PDGF, platelet-derived growth factor; PF4, platelet factor 4; PMN, neutrophil; ppbp, proplatelet basic protein; SDF, stromal cell–derived factor; SP1, sphingosine-1-phosphate; TGF, transforming growth factor; Th, T helper; TLR, toll-like receptor; TNF, tumor necrosis factor; TxA2, Thromboxane A2; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor.

This is the case of P-selectin, which is one of the most bioactive molecules contained in α-granules and involved in inflammation. It promotes platelet aggregation and platelet-endothelial and platelet-leukocyte interactions ^[19]. Other α-granule constituents such as PF4 or RANTES are immune mediators that recruit and activate immune cells or induce endothelial cell inflammation ^[20]^[21]. The inflammatory roles of most α-granule-derived chemokines, cytokines and adhesion molecules are well described. However, the direct contribution of dense granule constituents to immune responses is still largely unexplored. It is nevertheless known that serotonin, contained in dense granules, increases monocyte differentiation into dendritic cells (DCs) ^[22] and early naïve T-cell activation ^[23]. Moreover, platelets can recruit and activate DCs via integrin alphaMbeta2 (Mac-1) ^[24]. In addition, DC expression of T-cell co-stimulatory molecules CD80 and CD86 is increased by activated platelets in a contact-independent manner leading to a stronger and more rapid T-cell response ^[25]. In turn, T cells may activate platelets through a T-cell CD40L/platelet CD40 interaction leading to platelet release of RANTES and further T-cell recruitment ^[26]. Platelets are also the major source of soluble CD40L, which induces B-cell production of immunoglobulin (Ig)G, by activating DCs and promoting B-cell isotype switching ^[19]. It has also been suggested that platelets enhance signals needed for adaptive humoral immunity and germinal center formation ^[27].

Activated platelets also release interleukin-1β (IL-1β), which is not granule-stored but produced upon platelet stimulation ^[28]. Typical markers of platelet activation (granule exocytosis and integrin expression) are increased rapidly after platelet stimulation (seconds to minutes), but the release of IL-1β from stimulated platelets occurs over hours ^[29].

Platelets affect all phases of immune responses. Their interactions with immune cells likely mediate beneficial outcomes in limiting infection and maintaining hemostasis ^[30]. However, continued platelet interactions with leukocytes or endothelial cells can also lead to adverse effects from excessive immune stimulation and inflammatory insult ^[14].

3. Metabolic Plasticity of Platelets

Despite being small and lacking a nucleus, platelets possess extraordinary metabolic machinery. The metabolism of platelets is not fully known yet; however, it has been estimated that at their basal metabolic state, ATP is generated by both mitochondrial oxidative phosphorylation (OXPHOS) (35%) and glycolysis (65%) ^[31]. During platelet activation, fatty acid oxidation and glutaminolysis is promoted to meet the energetic needs for aggregation ^[31]. Fatty acids and L-glutamine are required for OXPHOS, and if necessary, platelets can uptake extracellular fatty acids ^[31]. Interestingly, platelets proved to have metabolic plasticity, which allows them to compensate the energetic demand driven by activation and aggregation switching from one to another metabolic route ^[31]. These two important ATP-generating pathways have become relevant in translational research, where it has been observed that severe phenotypes of allergic and respiratory diseases show a bioenergetic dysfunction in platelets and leukocytes ^[32]. As an example of dysfunction, decreased glycolytic function in platelets from asthmatic patients has shown to be compensated by increased tricarboxylic acid (TCA) cycle activity leading to a re-direction of their metabolism towards mitochondrial metabolism, which might increase oxidative injury in asthma ^[33].

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1. Platelets as Coagulation Factors

2. Platelets as Immune Mediators

3. Metabolic Plasticity of Platelets

References