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Apoptosis signal‐regulating kinase 1 regulates immune‐mediated thrombocytopenia, thrombosis, and systemic shock
Author(s) -
Patel Pravin,
Shaik Noor F.,
Zhou Yuhang,
Golla Kalyan,
McKenzie Steven E.,
Naik Ulhas P.
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.15049
Subject(s) - platelet , ask1 , microbiology and biotechnology , platelet activation , in vivo , biology , immunology , kinase , cancer research , protein kinase a , mitogen activated protein kinase kinase
Background Immune complexes (ICs) bind to and activate platelets via FcγRIIA, causing patients to experience thrombocytopenia, as well as an increased risk of forming occlusive thrombi. Although platelets have been shown to mediate IC‐induced pathologies, the mechanisms involved have yet to be fully elucidated. We identified that apoptosis signal‐regulating kinase 1 (ASK1) is present in both human and mouse platelets and potentiates many platelet functions. Objectives Here we set out to study ASK1's role in regulating IC‐mediated platelet functions in vitro and IC‐induced pathologies using an in vivo mouse model. Methods Using human platelets treated with an ASK1‐specific inhibitor and platelets from FCGR2A / Ask1 ‐/‐ transgenic mice, we examined various platelet functions induced by model ICs in vitro and in vivo. Results We found that ASK1 was activated in human platelets following cross‐linking of FcγRIIA using either anti‐hCD9 or IV.3 + goat‐anti‐mouse. Although genetic deletion or inhibition of ASK1 significantly attenuated anti‐CD9‐induced platelet aggregation, activation of the canonical FcγRIIA signaling targets Syk and PLCγ2 was unaffected. We further found that anti‐mCD9‐induced cPla 2 phosphorylation and TxA 2 generation is delayed in Ask1 null transgenic mouse platelets leading to diminished δ‐granule secretion. In vivo, absence of Ask1 protected FCGR2A transgenic mice from thrombocytopenia, thrombosis, and systemic shock following injection of anti‐mCD9. In whole blood microfluidics, platelet adhesion and thrombus formation on fibrinogen was enhanced by Ask1. Conclusions These findings suggest that ASK1 inhibition may be a potential target for the treatment of IC‐induced shock and other immune‐mediated thrombotic disorders.