Signal Transducer and Activator of Transcription 3 (STAT3) Regulates Collagen-Induced Platelet Aggregation Independently of Its Transcription Factor Activity

Abstract

Background Platelet hyperactivity induced by inflammation is a known risk factor for atherosclerosis and thrombosis, but its underlying mechanisms remain poorly understood. Methods and Results The signal transducers and activators of transcription 3 (STAT3) was activated in collagen-stimulated platelets. Activated STAT3 served as a protein scaffold to facilitate the catalytic interaction between the kinase Syk and the substrate PLCγ2 to enhance collagen-induced calcium mobilization and platelet activation. The same interaction of STAT3 with Syk and PLCγ2 was also detected in HEK293 cells transfected with cDNAs for Syk and PLCγ2, and stimulated with interleukin-6 (IL-6). Pharmacological inhibition of STAT3 blocked ~50% of collagen- and a collagen-related peptide-, but not TRAP- or ADP-induced aggregation and ~80% of thrombus formation of human platelets on a collagen matrix. This in vitro phenotype was reproduced in mice infused with STAT3 inhibitors and mice with platelet specific STAT3 deficiency. By forming a complex with its soluble receptor, the proinflammatory cytokine IL-6 enhanced the collagen-induced STAT3 activation in human platelets. Conclusions These data demonstrate a non-transcriptional activity of STAT3 that facilitates a crosstalk between proinflammatory cytokine and hemostasis/thrombosis signals in platelets. This crosstalk may be responsible for platelet hyperactivity found in conditions of inflammation.

Activated Platelets Induce Endothelial Cell Activation via an Interleukin-1β Pathway in Systemic Lupus Erythematosus

“…Recently, platelet activity has been shown to be regulated by the JAK/STAT3 signaling axis, independent of STAT3 transcription factor activity. 50,51 STAT3 inhibition may be useful in not only attenuating platelet activation but also modulating the downstream effects on endothelial cell activation in the pathogenesis of SLE-accelerated atherosclerosis.…”

Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation

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Platelet Immunoreceptor Tyrosine-Based Activation Motif (ITAM) Signaling and Vascular Integrity

“…Genetic deficiency in mice of any of the proteins mentioned above leads to severely impaired ITAM signaling in platelets. Other adapters and effectors that associate with the ITAM signalosome, such as Signal Transducer and Activator of Transcription 3 (STAT3) 46 , the small GTPase Rac1 47, 48, 49 and its exchange factors Vav1 and Vav3 50–52 , the tyrosine kinases Btk 53 and Tec 54 , or various PI3 kinase isoforms 55 also contribute to effective signaling. Downstream of PLCγ2, the small GTPase Rap1 orchestrates various cellular responses, including integrin activation 56, 57, 58 TxA 2 formation 59 , and granule release 49, 60 .…”