美国波士顿儿童医院Ivan Zanoni研究组发现在活化血小板中抑制转录因子NFAT的活性增强了血小板聚集，并加剧了由革兰氏阴性细菌引发的败血症。该项研究成果发表在2022年1月6日出版的《免疫》上。

研究人员发现凝血酶信号诱导血小板中转录因子NFAT的激活。使用遗传和药理学方法，以及新开发的小鼠模型iNFATuation，该小鼠可抑制细胞特异性NFAT激活，研究人员发现在激活的小鼠和人血小板中，抑制NFAT增强了血小板的激活和聚集，以及它们与中性粒细胞和性粒细胞胞外陷阱 (NET)诱导的相互作用。在革兰氏阴性菌诱导的败血症中，抑制血小板中NFAT通过增加弥散性凝血和NETosis增加了疾病的严重程度。NFAT抑制也部分恢复了血小板活性减退患者的体外凝血。该研究结果揭示了NFAT的非转录作用，可用于解决紧迫的临床需求。

据悉，在由革兰氏阴性菌诱导的败血症中，血小板和中性粒细胞之间的相互作用诱导了一个有害的反馈回路，导致持续性NET 、弥散性血管内凝血和炎症。了解控制血小板-中性粒细胞相互作用的细胞内途径对于确定新的治疗靶点至关重要。

附：英文原文

Title: Inhibition of transcription factor NFAT activity in activated platelets enhances their aggregation and exacerbates gram-negative bacterial septicemia

Author: Valentina Poli, Marco Di Gioia, Martha Sola-Visner, Francesca Granucci, Andrew L. Frelinger, Alan D. Michelson, Ivan Zanoni

Issue&Volume: 2022-01-06

Abstract: During gram-negative septicemia, interactions between platelets and neutrophils initiatea detrimental feedback loop that sustains neutrophil extracellular trap (NET) induction,disseminated intravascular coagulation, and inflammation. Understanding intracellularpathways that control platelet-neutrophil interactions is essential for identifyingnew therapeutic targets. Here, we found that thrombin signaling induced activationof the transcription factor NFAT in platelets. Using genetic and pharmacologic approaches,as well as iNFATuation, a newly developed mouse model in which NFAT activation canbe abrogated in a cell-specific manner, we demonstrated that NFAT inhibition in activatedmurine and human platelets enhanced their activation and aggregation, as well as theirinteractions with neutrophils and NET induction. During gram-negative septicemia,NFAT inhibition in platelets promoted disease severity by increasing disseminatedcoagulation and NETosis. NFAT inhibition also partially restored coagulation ex vivo in patients with hypoactive platelets. Our results define non-transcriptional rolesfor NFAT that could be harnessed to address pressing clinical needs.

DOI: 10.1016/j.immuni.2021.12.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00535-5