2. Academic Validation
  3. Inhibition of transcription factor NFAT activity in activated platelets enhances their aggregation and exacerbates gram-negative bacterial septicemia

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.
Valentina Poli 1,  Marco Di Gioia 1,  Martha Sola-Visner 2,  Francesca Granucci 3,  Andrew L Frelinger 3rd 4,  Alan D Michelson 4,  Ivan Zanoni 5
Affiliations

Affiliations

  • 1 Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, MA, USA.
  • 2 Harvard Medical School, Boston Children's Hospital, Division of Newborn Medicine, Boston, MA, USA.
  • 3 Department of Biotechnology and Biosciences, University of Milano-Bicocca, INGM-National Institute of Molecular Genetics "Romeo ed Enrica Invernizzi", Milan, Italy.
  • 4 Center for Platelet Research Studies, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
  • 5 Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, MA, USA; Harvard Medical School, Boston Children's Hospital, Division of Gastroenterology, Boston, MA, USA. Electronic address: ivan.zanoni@childrens.harvard.edu.
PMID: 34995475 DOI: 10.1016/j.immuni.2021.12.002
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.

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