gms | German Medical Science

47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

04.09. - 07.09.2019, Dresden

Enhanced IL-7 receptor signaling in SLE promotes T-helper cell proliferation through upregulation of microRNA-182 and downregulation of FOXO1

Meeting Abstract

  • Tobias Alexander - Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
  • Claudia Haftmann - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • René Riedel - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Jens Humrich - Klinik für Rheumatologie und klinische Immunologie, Universitätsklinikum Schleswig-Holstein Campus Lübeck, Lübeck
  • Gerd-Rüdiger Burmester - Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
  • Andreas Radbruch - Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
  • Falk Hiepe - Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
  • Mir-Farzin Mashreghi - Deutsches Rheuma-Forschungszentrum (DRFZ), Arbeitsgruppe Zellbiologie, Berlin

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Gesellschaft für Kinder- und Jugendrheumatologie. 47. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 33. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 29. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR). Dresden, 04.-07.09.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocET.09

doi: 10.3205/19dgrh131, urn:nbn:de:0183-19dgrh1314

Published: October 8, 2019

© 2019 Alexander et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

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 analyzed 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 analyze 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.

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)-signaling 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 in CD4+ T cells by IL-7 even in absence of polyclonal activation.

Conclusion: Our data suggest that enhanced IL 7R/STAT5 signaling mediates the induction of miR 182 expression, which promotes the proliferation of conventional 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.