Platelet-Neutrophil aggregate formation induces NLRP3 inflammasome activation in VITT.

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-12-18 DOI:10.1016/j.jtha.2024.12.012
Remy Martins-Gonçalves, Stephane Vicente Rozini, Daniela P Mendes-de-Almeida, Lohanna Palhinha, Carolina Q Sacramento, Gean Carlo Pereira-Silva, Mariana M Campos, Douglas Mathias de Oliveira, Carlos A Lopes-Cardoso E Souza, Beatriz de Barros Gonçalves de Jesus, Isaclaudia Gomes de Azevedo-Quintanilha, Patricia Mouta Nunes de Oliveira, Renata Saraiva Pedro, Letícia Kegele Lignani, Gabriellen Vitiello Teixeira, Joanna Bokel, Sandra Wagner Cardoso, Brenda Hoagland, Elvira M Saraiva, Beatriz Grinsztejn, Maria de Lourdes de Sousa Maia, Luiz Amorim Filho, Eugenio D Hottz, Patricia T Bozza
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Abstract

Background: Although rare, vaccine-induced thrombotic thrombocytopenia (VITT) following adenoviral vector COVID-19 vaccination is a concerning and often severe adverse effect of vaccination. The generation of high anti-platelet factor 4 (PF4) antibody titers, promotes the formation of immune complexes capable of activating platelets and neutrophils through FcγRIIa.

Objective: Given that Platelet-leukocyte aggregate (PLA) formation and inflammasome activation are common features of thromboinflammatory diseases, we aimed to evaluate if these are also features of VITT.

Methods: Samples from a cohort of 57 postvaccination thrombosis patients and 28 age- and sex-matched unvaccinated individuals were used for ex-vivo investigation of PLA formation and inflammasome activation.

Results: Patients with clinical features of VITT presented elevated levels of activated caspase-1, IL-18 and IL-1β in the plasma. We also found that soluble factors in the plasma of VITT patients induce the formation of platelet-neutrophil aggregates but not platelet-monocyte or platelet-T-cell aggregates, which are associated with increased caspase-1 activation in neutrophils ex-vivo. Platelet-neutrophil aggregate formation was prevented through blockage of FcγRIIa with the neutralizing antibody IV.3, and through blockage of P-selectin or integrin αIIbβ3, also inhibiting caspase-1 activation. Additionally, MCC950, an NLRP3 inflammasome inhibitor, blocked caspase-1 activation.

Conclusions: Taken together, these data show that VITT plasma induces platelet-neutrophil aggregate formation in an FcγRIIa-dependent manner and that platelet-neutrophil interactions may contribute to thromboinflammation in VITT patients by supporting NLRP3 inflammasome activation. These data shed light on novel immunopathological events associated with inflammation and thrombosis in VITT patients.

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血小板-中性粒细胞聚集形成诱导VITT中NLRP3炎性体活化。
背景:虽然罕见,但腺病毒载体COVID-19疫苗接种后疫苗诱导的血栓性血小板减少症(VITT)是一种令人担忧的且往往严重的疫苗不良反应。高抗血小板因子4 (PF4)抗体滴度的产生,通过FcγRIIa促进能够激活血小板和中性粒细胞的免疫复合物的形成。目的:鉴于血小板-白细胞聚集(PLA)的形成和炎性体的激活是血栓炎性疾病的共同特征,我们旨在评估这些是否也是VITT的特征。方法:从57例接种疫苗后血栓患者和28例年龄和性别匹配的未接种疫苗个体中提取样本,进行PLA形成和炎性体激活的体外研究。结果:具有VITT临床特征的患者血浆中活化caspase-1、IL-18、IL-1β水平升高。我们还发现VITT患者血浆中的可溶性因子可诱导血小板-中性粒细胞聚集物的形成,但不能诱导血小板-单核细胞或血小板- t细胞聚集物的形成,这与体外中性粒细胞caspase-1激活增加有关。通过中和抗体IV.3阻断fc - γ - riia,通过阻断p -选择素或整合素α ib - β3,也可以抑制caspase-1的激活,从而阻止血小板-中性粒细胞聚集的形成。此外,NLRP3炎性体抑制剂MCC950可以阻断caspase-1的激活。综上所述,这些数据表明VITT血浆以fc γ riia依赖的方式诱导血小板-中性粒细胞聚集形成,血小板-中性粒细胞相互作用可能通过支持NLRP3炎性体激活而促进VITT患者的血栓炎症。这些数据揭示了VITT患者中与炎症和血栓形成相关的新的免疫病理事件。
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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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