RRC ID 48755
Author Richard EM, Thiyagarajan T, Bunni MA, Basher F, Roddy PO, Siskind LJ, Nietert PJ, Nowling TK.
Title Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism.
Journal PLoS One
Abstract Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1(+/+) or Fli1(+/-) T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1(+/-) lupus T cells compared to animals receiving Fli1(+/+) lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1(+/-) T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1(+/+) T cells. Moreover, the Fli1(+/-) T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1(+/+) T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus.
Volume 8(9)
Pages e75175
Published 2013-1-1
DOI 10.1371/journal.pone.0075175
PII PONE-D-13-11673
PMID 24040398
PMC PMC3769295
MeSH Adoptive Transfer Animals B-Lymphocytes / immunology B-Lymphocytes / metabolism Disease Models, Animal Disease Progression Female Glycosphingolipids / metabolism* Homeodomain Proteins / metabolism Humans Interleukin-4 / biosynthesis Jurkat Cells Lupus Erythematosus, Systemic / immunology* Lupus Erythematosus, Systemic / metabolism* Lymphocyte Activation Mice Mice, Inbred MRL lpr Proto-Oncogene Protein c-fli-1 / deficiency Proto-Oncogene Protein c-fli-1 / metabolism* Receptors, Antigen, T-Cell / metabolism T-Lymphocytes / immunology* T-Lymphocytes / metabolism*
IF 2.74
Times Cited 17
DNA material B6N BAC Mouse (RDB07573) B6Ng01-067D09