Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

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, 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-␥) 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.

Innate Immune Molecule Surfactant Protein D Attenuates Sepsis-induced Acute Pancreatic Injury through Modulating Apoptosis and NF-κB-mediated Inflammation

“…These data are supported by the increased NF-κB and p-IκB-α levels in the pancreas of septic WT and SP-D KO mice. Our findings are consistent with previous studies that demonstrated increased TNF-α and IL-6 in the serum during polymicrobial sepsis by CLP 57 58 . Additionally, in vitro experiments with isolated islet cultures stimulated by LPS demonstrated SP-D function in the modulation of inflammatory cytokine production in the islet cells.…”

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

“…Nevertheless, several studies using NFAT inhibitors for different immune-related disease models support that inhibition of the NFAT pathway can attenuate an immune response. [27][28][29][30][31][32] Moreover, among individuals with Down syndrome, the inhibition of the NFAT pathway (partly via overexpression of DYRK1A and DSCR1 due to trisomy 21) 33,34 is hypothesized to be related to the cardiac, neurologic, and immunologic defects associated with Down syndrome, 34 and individuals with Down syndrome may have attenuated antibody responses to several vaccine antigens. 35 Based on this role of the NFAT pathway in Down syndrome, and on our finding of a higher incidence of asparaginase hypersensitivity among those carrying the NFATC2 variant, we hypothesized that Down syndrome patients might have a lower incidence of asparaginase hypersensitivity.…”

Xenogeneic mesenchymal stem cell transplantation for mandibular defect regeneration

“…An overall weaker response in athymic rats can be explained by their lack of Th17 regulatory T helper cells, as neutrophil recruitment can be mediated by IL-17 and nuclear factor of activated T cells (NFAT). 23,24 It was also found that strong infiltration was not observed until day 3 in athymic rats but started at day 1 in immunocompetent rats (Figure 3). The delayed response in athymic rats may be caused by the administration of Meloxicam for pain control for all the animals.…”