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.
Highlights
Besides their central role in hemostasis, platelets have entered the field of immunity as inflammatory cells [1,2,3,4,5]
Supporting this finding from others [20], we observed that activation of human platelets with Thrombin receptor activator peptide (TRAP) did not significantly affect the baseline expression of TLR2; TRAP cannot be ascribed as over regulating TLR2 expression
These data support that a significant population of resting platelets express TLR2 on their surface and have the potential downstream effectors to mediate TLR2 signaling
Summary
Besides their central role in hemostasis, platelets have entered the field of immunity as inflammatory cells [1,2,3,4,5]. We found that stored platelets contain molecules with known immunomodulatory roles and differentially secrete them upon storage in blood banking conditions [8,9,10,11]. Platelet TLR2 Activation and Signaling Pathway platelet TLRs is TLR4. Recent studies by our group [12] and others [13, 14] support the idea that platelets are able to distinguish between membrane signaling molecules and can for instance, adapt their secretion to specific signals sensed via TLR4. We have shown that soluble (s)CD14 from plasma contributes to LPS/TLR4 signaling in platelets to allow the potent release of sCD40L, thereby elucidating the mechanism of LPS-induced platelet responses and providing new insights for reducing LPS toxicity in the circulation [15]
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