Академический Документы
Профессиональный Документы
Культура Документы
Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
Soluble factor secretion rotonin may also be important in human inflammation [reviewed
in (145)]. In fact numerous immunomodulatory functions of pe-
Infections and the role of plasma
Platelets have a number of immune and inflammatory features ripheral serotonin (which is mostly platelet-derived) have been
ranging from secretable immunomodulatory factors to stably or characterised, including differential effects on chemokine/cyto-
proteins and platelets
variably expressed surface receptors (summarised in ▶ Table 1). kine secretion by immune cells. ▶ Figure 1 summarises immune
Rapid secretion of a wide array of inflammatory mediators follow- effects of serotonin as one example of the complexity of platelet
ing exocytosis of α granules, dense granules, and lysosomes upon immunomodulation (24, 31, 91, 146–165).
activation is a unique feature of platelets. This enables an almost
instantaneous response to stimuli in the affected vasculature. Of
note, platelets not only contain preformed secretable factors, but
Lysosomes
are also capable of newly synthesizing mediators such as interleu- Lysosomes release glycosidases, proteases, and bactericidal
kin (IL)-1β following signal-dependent splicing of pre-mRNA enzymes such as β-glucuronidase, elastase, and collagenase [re-
(43). viewed in (46)]. The lysosome releasate facilitates pathogen clear-
ance and breakdown of extracellular matrix but current studies are
rare and clinical implications have not been addressed systemati-
α-granule factors cally.
α-granules are the most abundant granules in platelets and contain
a variety of inflammatory mediators, including a number of adhes-
ive proteins (45). Platelet aggregation and (micro-)thrombus
Defensins
formation are promoted by fibrinogen, von Willebrand factor Other secretable factors are not associated with any of the known
(VWF), fibronectin, vitronectin and serve as an immobilising ma- granules. They are either derived from cytoplasmic stores, are
trix for pathogen capture [reviewed in (21, 44, 45)]. Theoretically, newly synthesised proteins, or are components of a yet unknown
this limits pathogen growth and multiplication in the vasculature type of granule. β-defensin is an example of granule-independent
and facilitates exposure of these captured pathogens to neutralis- mediators with anti-bactericidal activity (107) and belongs to the
ing leukocytes. Although this pathophysiologic sequence has not group of antimicrobial peptides. Human platelets express β-de-
been deciphered directly in mechanistic studies, observations in fensins 1, 2, and 3 (107, 166, 167). Platelets release β-defensin 1
septic patients (and mice) suggest that platelet aggregation is not from cytoplasm in response to Staphylococcus aureus α-toxin to in-
only a complication but rather a feature of primary host defense duce neutrophil extracellular trap (NET) formation and limit bac-
(17). Platelet factor 4 (PF4, CXCL4) and the β-thromboglobulin terial growth (107).
neutrophil-activating protein 2 (NAP2, CXCL7) regulate neutro-
phil and monocyte functions and promote their recruitment (89).
PF4 furthermore suppresses neutrophil apoptosis, which was dem- Immune receptors
onstrated in a platelet depletion study of murine limb ischaemia
(140). Several α-granule-derived chemokines have been studied Different immune receptors operate on the platelet surface (and in
extensively, especially in atherogenesis, and are considered impor- some cases intracellularly) [reviewed in (168)]. Toll-like receptors
tant messengers of immune functions [reviewed in (141)]. Che- recognise pathogen- and danger-associated molecular patterns
mokine functions include chemotaxis and modulation of different (PAMPs and DAMPS, respectively) [reviewed in (6)], complement
leukocyte functions. Platelets are able to take up immunoglobulins receptors mediate complement activation at sites of platelet ac-
from plasma to store them in α-granules and to release this cargo cumulation (169), and Fc receptors recognising immunoglobulins
on-site following inflammatory stimulation (44, 142) [reviewed in (FcR, notably the Fcγ receptor FcγRIIA, but also Fcα and Fcε re-
(44)]. This interesting observation may represent a contribution of ceptors) provide a link to the adaptive immune system (79, 170).
platelets to humoral immunity. In a murine model of Arthus reaction, platelets facilitate the im-
mune complex-induced recruitment of neutrophils in microvessels
(171). P-selectin on activated platelets appears to participate in
Dense granule factors complement activation and platelet-associated immune complexes
Dense granules store serotonin, calcium, magnesium, ATP, and mediate autoimmune diseases such as immune thrombocytopenia
ADP (whether they also contain histamine is controversial [93, or systemic lupus erythematosus (23, 79). C-type lectin-like recep-
143]) and secrete these factors upon activation (reviewed in [143, tor 2 (CLEC-2) is involved in the regulation of vascular integrity in
144]). At the site of acute inflammation platelets release serotonin acute inflammation (119, 172).
at micromolar concentrations, boosting the recruitment of neutro-
phils into the inflamed tissue during murine pneumonia, peritoni-
tis, and skin wounds (91). In mice, this translates into improved
CD40 / CD40 ligand
sepsis outcome when platelet serotonin stores were depleted. The With cell activation differentially regulating their surface presenta-
observation that antidepressants inhibiting the uptake of serotonin tion, CD40 and CD40L are not only expressed by platelets, but also
modulate the release of several cytokines, suggests that platelet se- by endothelial cells, smooth muscle cells, and several leukocyte
Table 1: Immune and inflammatory platelet components [reviewed in (4, 7, 21, 44–46)].
Table 1: Continued
Infections and the role of plasma
Table 1: Continued
subtypes (4, 110, 125–129, 173–177) [reviewed in (4, 128, 129, 173, sively studied platelet TLRs (121, 182–184). Platelets also contain
174)]. This inflammatory axis mediates complex cell-cell interac- the adapter molecules MYD88 and TRIF required for specific
tions. CD40/CD40L-mediated interactions have been well charac- downstream signalling (185, 186). The TLR2/1-specific agonist
terised in atherosclerosis, but are likely also involved in several Pam3CSK4 has been utilised by different groups to stimulate pla-
other immune reactions. Platelets release CD40L and RANTES telets. It induces a dose-dependent response involving different in-
upon stimulation with IgG complexes without showing signs of tracellular signalling pathways, which may be part of defense
general activation (80). Platelet CD40L triggers inflammatory acti- mechanisms against gram-positive bacteria (187, 188). Stimu-
vation of endothelium: it induces upregulation of E-selectin, lation of platelet TLR4 has been linked to NET formation and sub-
ICAM-1, and VCAM-1 and provokes chemokine secretion by en- sequent capture of gram-negative bacteria in the blood stream
dothelial cells (178). (189). Platelet TLR7 binds viral RNA triggering PNC formation in
mice, improving the animals’ survival (123). Platelet TLR9 recog-
nises viral and bacterial DNA and promotes platelet reactivity
Toll-like receptors (182, 190). Finally, TLR9 mediated protection from atherosclerosis
Platelets express functional TLRs and respond to ligand binding in mice by suppressing the influx of CD4+ T cells into plaques
and activation (179–181) [reviewed in (122)]. TLR2 and TLR4 and (124). Platelet TLRs are an interesting target for future therapeutic
the predominately intracellular TLR9 (182) are the most exten- studies because pharmacological manipulation is uncomplicated.
[reviewed in (173, 174)]. Platelet-derived sCD40L induces reactive have been divided into four major functional classes: leukocyte
oxygen species (ROS) production, neutrophil adhesion receptor modulation, leukocyte recruitment, pathogen capture, and pa-
upregulation, macrophage activation, and cytotoxic T cell and B thogen killing [reviewd in (44)]. ▶ Table 2 allocates mechanisms
cell stimulation [reviewed in (21)]. CD40L can also be carried by to these four classes.
platelet microparticles, regulating antigen-specific IgG production
[reviewed in (21, 173)]. Whether platelet-derived sCD40L is ac-
cessible to pharmacological intervention remains to be shown. Interactions with endothelium and
leukocytes
TACE An early response to acute inflammation is the activation of en-
TNFα converting enzyme (TACE, ADAM17) is a sheddase ex- dothelium in affected vessels. This induces platelet and leukocyte
pressed not only by neutrophils (where it regulates shedding of interactions with the vessel wall resulting in rolling, adhesion, and
L-selectin and pro-TNFα), but also by platelets (191, 192). Numer- transmigration into the inflamed organ [reviewed in (10, 208)].
ous signals can activate TACE, including atherosclerotic plaque During inflammatory cell recruitment, platelets and leukocytes
components (193, 194). Although specific immune functions of also closely interact with each other and form platelet-leukocyte
platelet surface TACE have not yet been deciphered, it is intriguing complexes, predominantly PNCs and PMCs (▶ Figure 2) (17, 209,
to note that oxidative stress and serotonin receptor activation in- 210) [reviewed in (21)]. A key mediator is P-selectin, which is ex-
duce GPIbα and GPV shedding by TACE (132, 191, 195–197). posed on the platelet surface after α granule exocytosis and then
binds leukocyte PSGL-1 [reviewed in (45)].
Figure 1: An exemplary illustration of the complexity of platelet immunity. Inflammatory secretion of platelet (or in some cases neuronal) seroto-
nin provokes a wide array of differential effects on immune cells.
Table 2: Immune and inflammatory functions of platelets [reviewed in (4, 7, 21, 44)].
Other important adhesion molecules mediating cell-cell inter- telet-monocyte interactions are mediated and controlled by the co-
actions are integrins and surface glycoproteins. Platelets express stimulatory CD40/CD40L axis (126, 129) [reviewed in (129)].
several β1 and β3 integrins, including integrins α5β1 and α2bβ3 During endotoxaemia, platelets tether and roll on endothelium
(GPIIb/IIIa) [reviewed in (168, 211)]. Integrin ligands on leuko- and subendothelium via GPIbα and P-selectin, followed by GPIIb/
cytes are intercellular adhesion molecule (ICAM) and junctional IIIa-mediated firm adhesion [reviewed in (10, 48, 212)]. This sub-
adhesion molecules (JAMs) [reviewed in (45, 48, 212)]. Fur- sequently induces PSGL-1-mediated rolling of neutrophils on the
thermore, GPIbα of the GPIb/IX/V receptor complex interacts di- P-selectin-expressing platelet layer. Neutrophil Mac-1 captures fi-
rectly with Mac-1 on monocytes and neutrophils (205) and GPVI brinogen, which is presented by platelet GPIIb/IIIa and GPIbα, re-
mediates platelet recruitment and activation after collagen expo- sulting in neutrophil adhesion, a sequence of neutrophil recruit-
sure facilitating secondary leukocyte capture [reviewed in (45)]. ment that was recently deciphered in a murine model of encepha-
Increased PNC and PMC circulation was observed in patients lomyelitis (215). Accordingly, the infusion of lipopolysaccharide
with sepsis, atherosclerosis, inflammatory bowel disease, and into humans induces PNC and PMC formation (216, 217). In
cystic fibrosis (17, 44, 213) [reviewed in (44, 214)]. Finally, pla- summary, platelets closely interact with monocytes (218–220) and
telets (207). Both, HIV and S. aureus, were packed into engulfing
vacuoles that eventually fused with α-granules, possibly neutralis-
proteins and platelets
Conflicts of interest 29. Pitchford SC, et al. Platelets are essential for leukocyte recruitment in allergic in-
flammation. J Allergy Clin Immunol 2003; 112: 109–118.
None declared.
56. Hayward CP, et al. Factor V is complexed with multimerin in resting platelet ly- 83. Scheuerer B, et al. The CXC-chemokine platelet factor 4 promotes monocyte
sates and colocalizes with multimerin in platelet alpha-granules. J Biol Chem survival and induces monocyte differentiation into macrophages. Blood 2000;
Infections and the role of plasma
58. Hu CJ, et al. Tissue-specific expression of functional platelet factor XI is inde- 2005; 105: 924-930.
pendent of plasma factor XI expression. Blood 1998; 91: 3800-3807. 85. Struyf S, et al. Platelets release CXCL4L1, a nonallelic variant of the chemokine
59. Marx G, et al. Packaging zinc, fibrinogen, and factor XIII in platelet alpha-gran- platelet factor-4/CXCL4 and potent inhibitor of angiogenesis. Circ Res 2004; 95:
ules. J Cell Physiol 1993; 156: 437-442. 855-857.
60. Barrientos S, et al. Growth factors and cytokines in wound healing. Wound Re- 86. Fleischer J, et al. Platelet factor 4 inhibits proliferation and cytokine release of
pair Regen 2008; 16: 585–601. activated human T cells. J Immunol 2002; 169: 770-777.
61. Linder BL, et al. Release of platelet-derived growth factor from human platelets 87. Mei J, et al. CXCL5 regulates chemokine scavenging and pulmonary host de-
by arachidonic acid. Proc Natl Acad Sci USA 1979; 76: 4107-4111. fense to bacterial infection. Immunity 2010; 33: 106-117.
62. Lo Re S, et al. Platelet-derived growth factor-producing CD4+ Foxp3+ regula- 88. Power CA, et al. Cloning of a full-length cDNA encoding the neutrophil-activat-
tory T lymphocytes promote lung fibrosis. Am J Respir Crit Care Med 2011; ing peptide ENA-78 from human platelets. Gene 1994; 151: 333-334.
184: 1270-1281. 89. Brandt E, et al. The beta-thromboglobulins and platelet factor 4: blood platelet-
63. Fava RA, et al. Synthesis of transforming growth factor-beta 1 by megakaryo- derived CXC chemokines with divergent roles in early neutrophil regulation. J
cytes and its localisation to megakaryocyte and platelet alpha-granules. Blood Leukoc Biol 2000; 67: 471-478.
1990; 76: 1946-1955. 90. Hristov M, et al. Importance of CXC chemokine receptor 2 in the homing of
64. Pinzani M, et al. Effects of platelet-derived growth factor and other polypeptide human peripheral blood endothelial progenitor cells to sites of arterial injury.
mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Circ Res 2007; 100: 590-597.
Clin Invest 1989; 84: 1786-1793. 91. Duerschmied D, et al. Platelet serotonin promotes the recruitment of neutro-
65. Salgado R, et al. Platelets and vascular endothelial growth factor (VEGF): a mor- phils to sites of acute inflammation in mice. Blood 2013; 121: 1008-1015.
phological and functional study. Angiogenesis 2001; 4: 37–43. 92. Berger M, et al. The expanded biology of serotonin. Annu Rev Med 2009; 60:
66. Schmaier AH, et al. Expression of platelet C1 inhibitor. Blood 1993; 82: 465-474. 355-366.
67. Shieh BH, Travis J. The reactive site of human alpha 2-antiplasmin. J Biol Chem 93. Mannaioni PF, et al. Storage and release of histamine in human platelets. In-
1987; 262: 6055-6059. flamm Res 1995; 44 (Suppl 1): S16-17.
68. Nylander M, et al. The role of thrombin receptors PAR1 and PAR4 for PAI-1 94. King SM, et al. Platelet dense-granule secretion plays a critical role in thrombo-
storage, synthesis and secretion by human platelets. Thromb Res 2012; 129: sis and subsequent vascular remodeling in atherosclerotic mice. Circulation
e51-58. 2009; 120: 785-791.
69. Brogren H, et al. Platelets synthesize large amounts of active plasminogen acti- 95. Stefanini L, et al. CalDAG-GEFI is at the nexus of calcium-dependent platelet
vator inhibitor 1. Blood 2004; 104: 3943-3948. activation. Blood 2009; 114: 2506-2514.
70. Kwakman PH, et al. Native thrombocidin-1 and unfolded thrombocidin-1 exert 96. Evangelista V, et al. Platelet/polymorphonuclear leukocyte interaction in dy-
antimicrobial activity via distinct structural elements. J Biol Chem 2011; 286: namic conditions: evidence of adhesion cascade and cross talk between P-selec-
43506-43514. tin and the beta 2 integrin CD11b/CD18. Blood 1996; 88: 4183-4194.
71. George JN, et al. Immunoglobulin G is a platelet alpha granule-secreted protein. 97. Frelinger AL, 3rd, et al. The active metabolite of prasugrel inhibits ADP-stimu-
J Clin Invest 1985; 76: 2020-2025. lated thrombo-inflammatory markers of platelet activation: Influence of other
72. George JN. Platelet IgG: measurement, interpretation, and clinical significance. blood cells, calcium, and aspirin. Thromb Haemost 2007; 98: 192–200.
Progr Haemost Thromb 1991; 10: 97–126. 98. Weissmann G. The role of lysosomes in inflammation and disease. Annu Rev
73. Falet H, et al. Platelet-associated IgAs and impaired GPVI responses in platelets Med 1967; 18: 97–112.
lacking WIP. Blood 2009; 114: 4729-4737. 99. Sixma JJ, et al. Immuno-electron microscopical demonstration of lysosomes in
74. George JN, Saucerman S. Platelet IgG, IgA, IgM, and albumin: correlation of human blood platelets and megakaryocytes using anti-cathepsin D. Blood 1985;
platelet and plasma concentrations in normal subjects and in patients with ITP 65: 1287-1291.
or dysproteinemia. Blood 1988; 72: 362-365. 100. Radzun HJ, et al. Lysosomal acid phosphatase: activity and isoenzymes in sep-
75. Berditchevski F, et al. Specific association of CD63 with the VLA-3 and VLA-6 arated normal human blood cells. Clin Chim Acta 1980; 102: 227-235.
integrins. J Biol Chem 1995; 270: 17784-17790. 101. Chesney CM, et al. Human platelet collagenase. J Clin Invest 1974; 53:
76. Damas C, et al. The 33-kDa platelet alpha-granule membrane protein (GMP-33) 1647-1654.
is an N-terminal proteolytic fragment of thrombospondin. Thromb Haemost 102. Chappell D, et al. Heparinase selectively sheds heparan sulphate from the en-
2001; 86: 887-893. dothelial glycocalyx. Biol Chem 2008; 389: 79–82.
77. Gear AR, Camerini D. Platelet chemokines and chemokine receptors: linking 103. Dangelmaier CA, Holmsen H. Determination of acid hydrolases in human pla-
haemostasis, inflammation, and host defense. Microcirculation 2003; 10: telets. Analyt Biochem 1980; 104: 182-191.
335-350. 104. Beaulieu LM, et al. Interleukin 1 Receptor 1 and Interleukin 1beta Regulate
78. Al-Bannawi A, et al. Chlamydia pneumoniae induces chemokine expression by Megakaryocyte Maturation, Platelet Activation, and Transcript Profile During
platelets in patients with atherosclerosis. Medical principles and practice : inter- Inflammation in Mice and Humans. Arterioscler Thromb Vasc Biol 2014; Epub
national journal of the Kuwait University, Health Science Centre 2011; 20: ahead of print.
438-443. 105. Maugeri N, et al. Circulating platelets as a source of the damage-associated mo-
79. Hasegawa S, et al. A comparison of FcepsilonRI-mediated RANTES release lecular pattern HMGB1 in patients with systemic sclerosis. Autoimmunity
from human platelets between allergic patients and healthy individuals. Int Arch 2012; 45: 584-587.
Allergy Immunol 2001; 125 (Suppl 1): 42-47. 106. Rouhiainen A, et al. Occurrence of amphoterin (HMG1) as an endogenous
80. Antczak AJ, Singh N, Gay SR, et al. IgG-complex stimulated platelets: a source of protein of human platelets that is exported to the cell surface upon platelet acti-
sCD40L and RANTES in initiation of inflammatory cascade. Cell Immunol vation. Thromb Haemost 2000; 84: 1087-1094.
2010; 263: 129-133. 107. Kraemer BF, et al. Novel anti-bacterial activities of beta-defensin 1 in human
81. von Hundelshausen P, et al. RANTES deposition by platelets triggers monocyte platelets: suppression of pathogen growth and signaling of neutrophil extracel-
arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103: lular trap formation. PLoS Pathogens 2011; 7: e1002355.
1772-177. 108. Prancan A, et al. Platelet thromboxane production during endotoxin shock.
82. Smith DF, et al. GRO family chemokines are specialized for monocyte arrest Agents Actions 1981; 11: 648-650.
from flow. Am J Physiol Heart Circ Physiol 2005; 289: H1976-1984. 109. Edwards LJ, Constantinescu CS. Platelet activating factor/platelet activating
factor receptor pathway as a potential therapeutic target in autoimmune dis-
eases. Inflam Allergy Drug Targets 2009; 8: 182-190.
110. Aukrust P, et al. Enhanced levels of soluble and membrane-bound CD40 ligand 136. Peerschke EI, et al. Platelet activation by C1q results in the induction of alpha
in patients with unstable angina. Possible reflection of T lymphocyte and pla- IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and proco-
164. Cloez-Tayarani I, et al. Differential effect of serotonin on cytokine production 190. Panigrahi S, et al. Engagement of platelet toll-like receptor 9 by novel endogen-
in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: ous ligands promotes platelet hyperreactivity and thrombosis. Circ Res 2013;
Infections and the role of plasma
on the production of tumor necrosis factor alpha and interleukin-6. Psychiatry 192. Black RA, et al. A metalloproteinase disintegrin that releases tumour-necrosis
Res 2005; 134: 251-258. factor-alpha from cells. Nature 1997; 385: 729-733.
166. Tohidnezhad M, et al. Platelets display potent antimicrobial activity and release 193. Canault M, et al. Microparticles of human atherosclerotic plaques enhance the
human beta-defensin 2. Platelets 2012; 23: 217-223. shedding of the tumor necrosis factor-alpha converting enzyme/ADAM17 sub-
167. Tohidnezhad M, et al. Thrombocytes are effectors of the innate immune system strates, tumor necrosis factor and tumor necrosis factor receptor-1. Am J Path-
releasing human beta defensin-3. Injury 2011; 42: 682-686. ol 2007; 171: 1713-1723.
168. Kasirer-Friede A, et al. Platelet integrins and immunoreceptors. Immunol Rev 194. Canault M, et al. The TNF alpha converting enzyme (TACE/ADAM17) is ex-
2007; 218: 247-264. pressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: possi-
169. Peerschke EI, et al. Platelet mediated complement activation. Adv Exp Med ble contribution to elevated plasma levels of soluble TNF alpha receptors.
Biol 2008; 632: 81–91. Atherosclerosis 2006; 187: 82–91.
170. Ginsberg MH, Henson PM. Enhancement of platelet response to immune 195. Duerschmied D, et al. Serotonin stimulates platelet receptor shedding by tumor
complexes and IgG aggregates by lipid A-rich bacterial lipopolysaccharides. J necrosis factor-alpha-converting enzyme (ADAM17). J Thromb Haemost
Exp Med 1978; 147: 207-217. 2009; 7: 1163-1171.
171. Lister KJ, et al. Immune complexes mediate rapid alterations in microvascular 196. Peschon JJ, et al. An essential role for ectodomain shedding in mammalian de-
permeability: roles for neutrophils, complement, and platelets. Microcircu- velopment. Science 1998; 282: 1281-1284.
lation 2007; 14: 709-722. 197. Brill A, et al. Oxidative stress activates ADAM17/TACE and induces its target
172. Suzuki-Inoue K. Essential in vivo roles of the platelet activation receptor receptor shedding in platelets in a p38-dependent fashion. Cardiovasc Res
CLEC-2 in tumour metastasis, lymphangiogenesis and thrombus formation. J 2009; 84: 137-144.
Biochem 2011; 150: 127-132. 198. Assinger A, et al. Efficient phagocytosis of periodontopathogens by neutrophils
173. Elzey BD, et al. Platelet CD40L at the interface of adaptive immunity. Thromb requires plasma factors, platelets and TLR2. J Thromb Haemost 2011; 9:
Res 2011; 127: 180-183. 799–809.
174. Ferroni P, et al. Contribution of platelet-derived CD40 ligand to inflammation, 199. Pamuk GE, et al. Increased circulating platelet-neutrophil, platelet-monocyte
thrombosis and neoangiogenesis. Curr Med Chem 2007; 14: 2170-2180. complexes, and platelet activation in patients with ulcerative colitis: a com-
175. Lutgens E, et al. Deficient CD40-TRAF6 signaling in leukocytes prevents parative study. Am J Hematol 2006; 81: 753-759.
atherosclerosis by skewing the immune response toward an antiinflammatory 200. Braun OO, et al. Greater reduction of platelet activation markers and platelet-
profile. J Exp Med 2010; 207: 391–404. monocyte aggregates by prasugrel compared to clopidogrel in stable coronary
176. Zirlik A, et al. TRAF-1, –2, –3, –5, and –6 are induced in atherosclerotic artery disease. Thromb Haemost 2008; 100: 626-633.
plaques and differentially mediate proinflammatory functions of CD40L in en- 201. da Costa Martins P, et al. Platelet-monocyte complexes support monocyte ad-
dothelial cells. Arterioscler Thromb Vasc Biol 2007; 27: 1101-1107. hesion to endothelium by enhancing secondary tethering and cluster
177. Lutgens E, et al. CD40L-CD40 fuel ignites obesity. Thromb Haemost 2010; 103: formation. Arterioscler Thromb Vasc Biol 2004; 24: 193-199.
694-695. 202. Sanderson HM, et al. Role of GPIIb-IIIa in platelet-monocyte and platelet-
178. Henn V, et al. CD40 ligand on activated platelets triggers an inflammatory neutrophil conjugate formation in whole blood. Platelets 1998; 9: 245-250.
reaction of endothelial cells. Nature 1998; 391: 591-594. 203. Herr N, et al. Acute fluoxetine treatment induces slow rolling of leukocytes on
179. Andonegui G, et al. Platelets express functional Toll-like receptor-4. Blood endothelium in mice. PLoS One 2014; 9: e88316.
2005; 106: 2417-2423. 204. Weber C, Springer TA. Neutrophil accumulation on activated, surface-adher-
180. Rex S, et al. Immune versus thrombotic stimulation of platelets differentially ent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound
regulates signalling pathways, intracellular protein-protein interactions, and to alphaIIbbeta3 and stimulated by platelet-activating factor. J Clin Invest 1997;
alpha-granule release. Thromb Haemost 2009; 102: 97–110. 100: 2085-2093.
181. Blair P, et al. Stimulation of Toll-like receptor 2 in human platelets induces a 205. Simon DI, et al. Platelet glycoprotein ibalpha is a counterreceptor for the leuko-
thromboinflammatory response through activation of phosphoinositide 3-ki- cyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193–204.
nase. Circ Res 2009; 104: 346-354. 206. Kastrup CJ, et al. Spatial localisation of bacteria controls coagulation of human
182. Thon JN, et al. T granules in human platelets function in TLR9 organisation blood by ’quorum acting’. Nature chemical biology 2008; 4: 742-750.
and signaling. J Cell Biol 2012; 198: 561-574. 207. Youssefian T, et al. Host defense role of platelets: engulfment of HIV and Sta-
183. Cognasse F, et al. Evidence of Toll-like receptor molecules on human platelets. phylococcus aureus occurs in a specific subcellular compartment and is en-
Immunol Cell Biol 2005; 83: 196-198. hanced by platelet activation. Blood 2002; 99: 4021-4029.
184. Aslam R, et al. Platelet Toll-like receptor expression modulates lipopolysac- 208. Zarbock A, et al. Leukocyte ligands for endothelial selectins: specialized glyco-
charide-induced thrombocytopenia and tumor necrosis factor-alpha produc- conjugates that mediate rolling and signaling under flow. Blood 2011; 118:
tion in vivo. Blood 2006; 107: 637-641. 6743-6751.
185. Berthet J, et al. Human platelets can discriminate between various bacterial 209. Sarma J, et al. Increased platelet binding to circulating monocytes in acute cor-
LPS isoforms via TLR4 signaling and differential cytokine secretion. Clin Im- onary syndromes. Circulation 2002; 105: 2166-2171.
munol 2012; 145: 189–200. 210. Clark RA, Klebanoff SJ. Neutrophil-platelet interaction mediated by myeloper-
186. Zhang G, et al. Lipopolysaccharide stimulates platelet secretion and potentiates oxidase and hydrogen peroxide. J Immunol 1980; 124: 399–405.
platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase 211. Nieswandt B, et al. Integrins in platelet activation. J Thromb Haemost 2009; 7
pathway. J Immunol 2009; 182: 7997–8004. (Suppl 1): 206-209.
187. Falker K, et al. The toll-like receptor 2/1 (TLR2/1) complex initiates human 212. van Gils JM, et al. Molecular and functional interactions among monocytes,
platelet activation via the src/Syk/LAT/PLCgamma2 signalling cascade. Cell platelets, and endothelial cells and their relevance for cardiovascular diseases. J
Signal 2014; 26: 279-286. Leukoc Biol 2009; 85: 195–204.
188. Rivadeneyra L, et al. Regulation of platelet responses triggered by Toll-like re- 213. Michelson AD. Methods for the measurement of platelet function. Am J Car-
ceptor 2 and 4 ligands is another non-genomic role of nuclear factor-kappaB. diol 2009; 103 (3 Suppl): 20A-26A.
Thromb Res 2014; 133: 235-243. 214. Michelson AD. Platelet function testing in cardiovascular diseases. Circulation
189. Clark SR, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare 2004; 110: e489-493.
bacteria in septic blood. Nat Med 2007; 13: 463-469. 215. Langer HF, et al. Platelets contribute to the pathogenesis of experimental auto-
immune encephalomyelitis. Circ Res 2012; 110: 1202-1210.
216. Wilson M, et al. Effects in humans of intravenously administered endotoxin on 227. Fuchs TA, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad
soluble cell-adhesion molecule and inflammatory markers: a model of human Sci USA 2010; 107: 15880–15885.