title: NF-κB Links TLR2 and PAR1 to Soluble Immunomodulator Factor Secretion in Human Platelets.
abstract: The primary toll-like receptor (TLR)-mediated immune cell response pathway common for all TLRs is MyD88-dependent activation of NF-κB, a seminal transcription factor for many chemokines and cytokines. Remarkably, anucleate platelets express the NF-κB machinery, whose role in platelets remains poorly understood. Here, we investigated the contribution of NF-κB in the release of cytokines and serotonin by human platelets, following selective stimulation of TLR2 and protease activated receptor 1 (PAR1), a classical and non-classical pattern-recognition receptor, respectively, able to participate to the innate immune system. We discovered that platelet PAR1 activation drives the process of NF-κB phosphorylation, in contrast to TLR2 activation, which induces a slower phosphorylation process. Conversely, platelet PAR1 and TLR2 activation induces similar ERK1/2, p38, and AKT phosphorylation. Moreover, we found that engagement of platelet TLR2 with its ligand, Pam3CSK4, significantly increases the release of sCD62P, RANTES, and sCD40L; this effect was attenuated by incubating platelets with a blocking anti-TLR2 antibody. This effect appeared selective since no modulation of serotonin secretion was observed following platelet TLR2 activation. Platelet release of sCD62P, RANTES, and sCD40L following TLR2 or PAR1 triggering was abolished in the presence of the NF-κB inhibitor Bay11-7082, while serotonin release following PAR1 activation was significantly decreased. These new findings support the concept that NF-κB is an important player in platelet immunoregulations and functions.
authors.affiliation: GIMAP-EA3064, Université de Lyon , Saint-Étienne , France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Damien
authors.affiliation: GIMAP-EA3064, Université de Lyon, Saint-Étienne, France; Etablissement Français du Sang Rhône-Alpes-Auvergne, Saint-Etienne, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Cognasse
authors.affiliation: Inserm, U1048 and Université Toulouse 3, I2MC, CHU de Toulouse, Laboratoire d'Hématologie , Toulouse , France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry , Rochester, NY , USA.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Spinelli
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry , Rochester, NY , USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Blumberg
authors.affiliation: Etablissement Français du Sang Rhône-Alpes-Auvergne , Saint-Etienne , France.
authors.forename: Charles-Antoine
authors.initials: CA
authors.lastname: Arthaud
authors.affiliation: Etablissement Français du Sang Rhône-Alpes-Auvergne , Saint-Etienne , France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Eyraud
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry , Rochester, NY , USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.affiliation: Faculty of Pharmacy, University of Manitoba , Winnipeg, MB , Canada.
authors.forename: Archibald
authors.initials: A
authors.lastname: McNicol
authors.affiliation: GIMAP-EA3064, Université de Lyon , Saint-Étienne , France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pozzetto
authors.affiliation: GIMAP-EA3064, Université de Lyon, Saint-Étienne, France; Institut National de Transfusion Sanguine (INTS), Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Garraud
authors.affiliation: GIMAP-EA3064, Université de Lyon , Saint-Étienne , France.
authors.forename: Hind
authors.initials: H
authors.lastname: Hamzeh-Cognasse
keywords: NF-κB; TLR2; cytokine/chemokine; inflammation; phosphorylation; platelets