生物
NFAT公司
细胞生物学
转录因子
微生物学
败血症
作者
Valentina Poli,Marco Di Gioia,Martha Sola-Visner,Francesca Granucci,Andrew L Frelinger,Alan D Michelson,Ivan Zanoni
出处
期刊:Immunity
[Elsevier]
日期:2021-12-24
被引量:1
标识
DOI:10.1016/j.immuni.2021.12.002
摘要
During gram-negative septicemia, interactions between platelets and neutrophils initiate a detrimental feedback loop that sustains neutrophil extracellular trap (NET) induction, disseminated intravascular coagulation, and inflammation. Understanding intracellular pathways that control platelet-neutrophil interactions is essential for identifying new therapeutic targets. Here, we found that thrombin signaling induced activation of the transcription factor NFAT in platelets. Using genetic and pharmacologic approaches, as well as iNFATuation, a newly developed mouse model in which NFAT activation can be abrogated in a cell-specific manner, we demonstrated that NFAT inhibition in activated murine and human platelets enhanced their activation and aggregation, as well as their interactions with neutrophils and NET induction. During gram-negative septicemia, NFAT inhibition in platelets promoted disease severity by increasing disseminated coagulation and NETosis. NFAT inhibition also partially restored coagulation ex vivo in patients with hypoactive platelets. Our results define non-transcriptional roles for NFAT that could be harnessed to address pressing clinical needs.
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