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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4452446
- author
- Zhang, Su
LU
; Luo, Lingtao
; Wang, Yongzhi
LU
; Gomez, Maria
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2014
- 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
- pmid:24866796
- 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
- 2016-04-01 10:53:22
- date last changed
- 2025-10-14 13:13:36
@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}},
doi = {{10.1128/IAI.01569-14}},
volume = {{82}},
year = {{2014}},
}