RT Journal Article
SR Electronic
T1 PS5:90 Enhanced il-7 receptor signalling in sle promotes t-helper cell proliferation through upregulation of microrna-182 and downregulation of foxo1
JF Lupus Science & Medicine
JO Lupus Sci & Med
FD Lupus Foundation of America
SP A82
OP A82
DO 10.1136/lupus-2018-abstract.135
VO 5
IS Suppl 1
A1 T Alexander
A1 C Haftmann
A1 R Riedel
A1 L Templin
A1 G Burmester
A1 A Radbruch
A1 F Hiepe
A1 F Mashreghi
YR 2018
UL http://lupus.bmj.com/content/5/Suppl_1/A82.1.abstract
AB Background Recent reports have shown dysregulated microRNAs (miRNAs) in murine models of lupus, among them increased expression of microRNA-182 (miRNA-182), which has been demonstrated to target the transcription factor FOXO1 in activated murine CD4 +T cells, leading to spontaneous T cell activation and clonal expansion. Here we aimed to investigate the expression of miR-182 and FOXO1 in T cells from human SLE patients.Methods Expression levels of miR-182 were analysed with RT-PCR in purified peripheral blood CD4 +T cells from 9 patients with SLE and age/sex-matched healthy controls (HC). Multicolor flow cytometry was performed to analyse CD4 +T cell expression for FOXO1, Ki-67, Foxp3, the interleukin-7 receptor-α (CD127) and phosphorylated STAT-5a (pSTAT5). Analysis of serum IL-7 levels was performed with ELISA in 27 SLE patients and HC. Induction of miR-182 was assessed in vitro after polyclonal T cell stimulation in the presence of IL-7, and inhibition of T cell proliferation investigated using mir-182 antagomirs.Results MiRNA-182 was significantly upregulated in CD4 +T cells from SLE patients compared to HC, while the FOXO1 expression was significantly decreased. The percentage of proliferating Ki-67 +conventional Foxp3- CD4 +T cells (Tcons) was significantly higher in SLE compared to HC (3.85% vs 1.58%, p<0.001) and their basal pSTAT5 levels significantly enhanced, suggesting a recent stimulation with common gamma chain(γc)-signalling cytokines. SLE Tcons displayed decreased expression levels for the FOXO1 target gene CD127 (MFI 2021 vs 2553, p=0.049) and serum IL-7 levels were significantly higher in SLE compared to HC (17.0 pg/ml vs 10.2 pg/ml, p=0.001). In vitro, miR-182 could be induced by IL-7, and specific inhibition of miR-182 inhibited T cell proliferation and survival.Conclusion Our data suggest that enhanced IL 7R/STAT5 signalling mediates the induction of miR 182 expression, which promotes the proliferation of conventional Foxp3- T cells SLE. Collectively, our data provide new insights in the pathophysiology of T cell hyperactivity in SLE and identifies miR-182 as a candidate target for future therapeutic approaches.