title: FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain.
abstract: The ETS factor Friend leukemia virus integration 1 (FLI1) is a key modulator of lupus disease expression. Overexpressing FLI1 in healthy mice results in the development of an autoimmune kidney disease similar to that observed in lupus. Lowering the global levels of FLI1 in two lupus strains (Fli1(+/-)) significantly improved kidney disease and prolonged survival. T cells from MRL/lpr Fli1(+/-) lupus mice have reduced activation and IL-4 production, neuraminidase 1 expression, and the levels of the glycosphingolipid lactosylceramide. In this study, we demonstrate that MRL/lpr Fli1(+/-) mice have significantly decreased renal neuraminidase 1 and lactosylceramide levels. This corresponds with a significant decrease in the number of total CD3(+) cells, as well as CD4(+) and CD44(+)CD62L(-) T cell subsets in the kidney of MRL/lpr Fli1(+/-) mice compared with the Fli1(+/+) nephritic mice. We further demonstrate that the percentage of CXCR3(+) T cells and Cxcr3 message levels in T cells are significantly decreased and correspond with a decrease in renal CXCR3(+) cells and in Cxcl9 and Cxcl10 expression in the MRL/lpr Fli1(+/-) compared with the Fli1(+/+) nephritic mice. Our results suggest that reducing the levels of FLI1 in MRL/lpr mice may be protective against development of nephritis in part through downregulation of CXCR3, reducing renal T cell infiltration and glycosphingolipid levels.
authors.affiliation: Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Kamala P
authors.initials: KP
authors.lastname: Sundararaj
authors.affiliation: Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Thirumagal
authors.initials: T
authors.lastname: Thiyagarajan
authors.affiliation: Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Ivan
authors.initials: I
authors.lastname: Molano
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and.
authors.forename: Fahmin
authors.identifier: http://orcid.org/0000-0002-6505-1947
authors.initials: F
authors.lastname: Basher
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Powers
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Drake
authors.affiliation: Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425; nowling@musc.edu.
authors.forename: Tamara K
authors.identifier: http://orcid.org/0000-0002-1445-5415
authors.initials: TK
authors.lastname: Nowling
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D007790:Lactosylceramides / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009393:Nephritis / Q000188:drug therapy* / Q000276:immunology; D009439:Neuraminidase / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C515188:Cxcr3 protein, mouse; C497426:Fli1 protein, mouse; D006028:Glycosphingolipids; D007790:Lactosylceramides; D051789:Proto-Oncogene Protein c-fli-1; D054367:Receptors, CXCR3; C009744:CDw17 antigen; D009439:Neuraminidase