Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis
| Autor: | Su Zhang, Lingtao Luo, Henrik Thorlacius, Yongzhi Wang, Maria F. Gomez |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
T-Lymphocytes
Immunology Inflammation Peritonitis Biology Systemic inflammation Microbiology Sepsis Mice medicine Animals IL-2 receptor Interleukin 6 Host Response and Inflammation NFATC Transcription Factors Coinfection Animal Structures FOXP3 NFAT medicine.disease Infectious Diseases Neutrophil Infiltration Cancer research biology.protein Parasitology medicine.symptom |
| Zdroj: | Infection and Immunity. 82:3275-3288 |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.01569-14 |
| Popis: | 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, interleukin 6 (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 gamma interferon (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. All together, 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. |
| Databáze: | OpenAIRE |
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