title: Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism.
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.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Erin Morris
authors.initials: EM
authors.lastname: Richard
authors.forename: Thirumagal
authors.initials: T
authors.lastname: Thiyagarajan
authors.forename: Marlene A
authors.initials: MA
authors.lastname: Bunni
authors.forename: Fahmin
authors.initials: F
authors.lastname: Basher
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Roddy
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Nietert
authors.forename: Tamara K
authors.initials: TK
authors.lastname: Nowling
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006028:Glycosphingolipids / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D051789:Proto-Oncogene Protein c-fli-1 / Q000172:deficiency / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: C497426:Fli1 protein, mouse; D006028:Glycosphingolipids; D018398:Homeodomain Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein; D015847:Interleukin-4
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