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(Circulation Research. 2009;104:346.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Stimulation of Toll-Like Receptor 2 in Human Platelets Induces a Thromboinflammatory Response Through Activation of Phosphoinositide 3-Kinase

Price Blair, Sybille Rex, Olga Vitseva, Lea Beaulieu, Kahraman Tanriverdi, Subrata Chakrabarti, Chie Hayashi, Caroline A. Genco, Mark Iafrati, Jane E. Freedman

From the Whitaker Cardiovascular Institute (P.B., S.R., O.V., L.B., K.T., S.C., J.E.F.), Evans Department of Medicine; Department of Microbiology (C.H.); and Department of Medicine (C.A.G.), Section of Molecular Medicine, Boston University School of Medicine; and Department of Surgery (M.I.), Tufts–New England Medical Center, Boston, Mass.

Correspondence to Price Blair, 700 Albany St, Whitaker Cardiovascular Institute, W507, Boston, MA 02118-2526. E-mail blairp{at}bu.edu

Cells of the innate immune system use Toll-like receptors (TLRs) to initiate the proinflammatory response to microbial infection. Recent studies have shown acute infections are associated with a transient increase in the risk of vascular thrombotic events. Although platelets play a central role in acute thrombosis and accumulating evidence demonstrates their role in inflammation and innate immunity, investigations into the expression and functionality of platelet TLRs have been limited. In the present study, we demonstrate that human platelets express TLR2, TLR1, and TLR6. Incubation of isolated platelets with Pam₃CSK4, a synthetic TLR2/TLR1 agonist, directly induced platelet aggregation and adhesion to collagen. These functional responses were inhibited in TLR2-deficient mice and, in human platelets, by pretreatment with TLR2-blocking antibody. Stimulation of platelet TLR2 also increased P-selectin surface expression, activation of integrin _IIbβ₃, generation of reactive oxygen species, and, in human whole blood, formation of platelet–neutrophil heterotypic aggregates. TLR2 stimulation also activated the phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway in platelets, and inhibition of PI3-K significantly reduced Pam₃CSK4-induced platelet responses. In vivo challenge with live Porphyromonas gingivalis, a Gram-negative pathogenic bacterium that uses TLR2 for innate immune signaling, also induced significant formation of platelet–neutrophil aggregates in wild-type but not TLR2-deficient mice. Together, these data provide the first demonstration that human platelets express functional TLR2 capable of recognizing bacterial components and activating the platelet thrombotic and/or inflammatory pathways. This work substantiates the role of platelets in the immune and inflammatory response and suggests a mechanism by which bacteria could directly activate platelets.

Key Words: platelets • Toll-like receptors • innate immunity

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