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Maria Gomez

Maria Gomez

Professor

Maria Gomez

NFAT regulates neutrophil recruitment, systemic inflammation and T-cell dysfunction in abdominal sepsis.

Author

  • Su Zhang
  • Lingtao Luo
  • Yongzhi Wang
  • Maria Gomez
  • Henrik Thorlacius

Summary, in English

The signaling mechanisms regulating neutrophil recruitment, systemic inflammation and T-cell dysfunction in polymicrobial sepsis are not clear. This study explored the potential involvement of the calcium/calcineurin-dependent transcription factor, nuclear factor of activated T-cells (NFAT) in abdominal sepsis. Cecal ligation and puncture (CLP) triggered NFAT-dependent transcriptional activity in the lung, spleen, liver and aorta in NFAT-luciferase reporter mice. Treatment with the NFAT inhibitor A-285222 prior to CLP completely prevented sepsis-induced NFAT activation in all these organs. Inhibition of NFAT activity reduced sepsis-induced formation of CXCL1, CXCL2 and CXCL5 chemokines and edema as well as neutrophil infiltration in the lung. Notably, NFAT inhibition efficiently reduced the CLP-evoked increases in HMBG1, IL-6 and CXCL5 levels in plasma. Moreover, administration of A-285222 restored sepsis-induced T-cell dysfunction, as evidenced by markedly decreased apoptosis and restored proliferative capacity of CD4 T-cells. Along these lines, treatment with A-285222 restored IFN-γ and IL-4 levels in the spleen, which were markedly reduced in septic mice. CLP-induced formation of regulatory T-cells (CD4(+)CD25(+)Foxp3(+)) in the spleen was also abolished in A-285222-treated animals. Altogether, these novel findings suggest that NFAT is a powerful regulator of pathological inflammation and T-cell immune dysfunction in abdominal sepsis. Thus, our data suggest that NFAT signaling might be a useful target to protect against respiratory failure and immunosuppression in patients with sepsis.

Department/s

  • Surgery
  • Diabetic Complications
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2014

Language

English

Pages

3275-3288

Publication/Series

Infection and Immunity

Volume

82

Issue

8

Document type

Journal article

Publisher

American Society for Microbiology

Topic

  • Cardiac and Cardiovascular Systems
  • Surgery
  • Endocrinology and Diabetes

Status

Published

Research group

  • Surgery
  • Diabetic Complications

ISBN/ISSN/Other

  • ISSN: 1098-5522