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

Zhang, Su LU ; Luo, Lingtao; Wang, Yongzhi LU ; Gomez, Maria LU and Thorlacius, Henrik LU (2014) In Infection and Immunity 82(8). p.3275-3288
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Infection and Immunity
volume
82
issue
8
pages
3275 - 3288
publisher
American Society for Microbiology
external identifiers
  • pmid:24866796
  • wos:000339161400017
  • scopus:84904735486
ISSN
1098-5522
DOI
10.1128/IAI.01569-14
language
English
LU publication?
yes
id
8fbb541e-a708-4e28-9ede-e9cbd0ab8cc5 (old id 4452446)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24866796?dopt=Abstract
date added to LUP
2014-06-06 21:23:01
date last changed
2017-09-17 04:02:19
@article{8fbb541e-a708-4e28-9ede-e9cbd0ab8cc5,
  abstract     = {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.},
  author       = {Zhang, Su and Luo, Lingtao and Wang, Yongzhi and Gomez, Maria and Thorlacius, Henrik},
  issn         = {1098-5522},
  language     = {eng},
  number       = {8},
  pages        = {3275--3288},
  publisher    = {American Society for Microbiology},
  series       = {Infection and Immunity},
  title        = {NFAT regulates neutrophil recruitment, systemic inflammation and T-cell dysfunction in abdominal sepsis.},
  url          = {http://dx.doi.org/10.1128/IAI.01569-14},
  volume       = {82},
  year         = {2014},
}