title: 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-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.
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Sciences, Section of Vascular Excitation-Transcription Coupling, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Lund University, Lund, Sweden henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000825:Animal Structures / Q000276:immunology / Q000473:pathology; D000818:Animals; D060085:Coinfection / Q000276:immunology / Q000473:pathology; D007249:Inflammation; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020556:Neutrophil Infiltration; D010538:Peritonitis / Q000276:immunology* / Q000473:pathology*; D018805:Sepsis / Q000276:immunology* / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D050778:NFATC Transcription Factors