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

Immunity. 2022 Feb 8;55(2):224-236.e5. doi: 10.1016/j.immuni.2021.12.002. Epub 2022 Jan 6.

Abstract

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.

Keywords: NETs; coagulation; gram-negative bacteria; neutrophil extracellular traps; neutrophils; platelets; sepsis; septic shock.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Coagulation / drug effects
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Cell Communication / drug effects
  • Cytoplasmic Granules / metabolism
  • Disease Models, Animal
  • Extracellular Traps / metabolism
  • Humans
  • Inflammation
  • Mice
  • NFATC Transcription Factors / antagonists & inhibitors*
  • NFATC Transcription Factors / metabolism
  • Neutrophils / metabolism
  • Platelet Aggregation / drug effects*
  • Receptors, Thrombin / metabolism
  • Sepsis / metabolism
  • Sepsis / pathology*

Substances

  • NFATC Transcription Factors
  • Receptors, Thrombin