Dataset Information

Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype.

ABSTRACT: Psoriasis lesions are rich in IL-17-producing T cells as well as neutrophils, which release webs of DNA-protein complexes known as neutrophil extracellular traps (NETs). Because we and others have observed increased NETosis in psoriatic lesions, we hypothesized that NETs contribute to increased T helper type 17 (Th17) cells in psoriasis. After stimulating peripheral blood mononuclear cells with anti-CD3/CD28 beads for 7 days, we found significantly higher percentages of CD3+CD4+IL-17+ (Th17) cells in the presence versus absence of NETs, as assessed by flow cytometry, IL-17 ELISA, and IL17A/F and RORC mRNAs. Memory, but not naïve, T cells were competent and monocytes were required for CD3/CD28-mediated Th17 induction, with or without NETs. Th17 induction was enhanced by the T allele of rs33980500 (T/C), a psoriasis risk-associated variant in the TRAF3IP2 gene encoding the D10N variant of Act1, a key mediator of IL-17 signal transduction. Global transcriptome analysis of CD3/CD28-stimulated peripheral blood mononuclear cells by RNA sequencing confirmed the stimulatory effects of NETs, demonstrated NET-induced enhancement of cytokine gene expression, and verified that the effect of Act1 D10N was greater in the presence of NETs. Collectively, these results implicate NETs and the Act1 D10N variant in human Th17 induction from peripheral blood mononuclear cells, with ramifications for immunogenetic studies of psoriasis and other autoimmune diseases.

SUBMITTER: Lambert S

PROVIDER: S-EPMC7092801 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype.

Lambert Sylviane S Hambro Caely A CA Johnston Andrew A Stuart Philip E PE Tsoi Lam C LC Nair Rajan P RP Elder James T JT

The Journal of investigative dermatology 20181205 6

Psoriasis lesions are rich in IL-17-producing T cells as well as neutrophils, which release webs of DNA-protein complexes known as neutrophil extracellular traps (NETs). Because we and others have observed increased NETosis in psoriatic lesions, we hypothesized that NETs contribute to increased T helper type 17 (Th17) cells in psoriasis. After stimulating peripheral blood mononuclear cells with anti-CD3/CD28 beads for 7 days, we found significantly higher percentages of CD3<sup>+</sup>CD4<sup>+< ...[more]

PMID: 30528823

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Project description:Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.

Dataset Information

Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype.

Publications

Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype.

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