Ets Family Transcription Factor Fli-1 Promotes Leukocyte Recruitment and Production of IL-17A in the MRL/Lpr Mouse Model of Lupus Nephritis

The transcription factor Friend leukemia integration 1 (Fli-1) regulates the expression of numerous cytokines and chemokines and alters the progression of lupus nephritis in humans and in the MRL/MpJ-Faslpr (MRL/lpr) mouse model. Th17-mediated immune responses are notably important as they promote ongoing inflammation. The purpose of this study is to determine the impact of Fli-1 on expression of interleukin-17A (IL-17A) and the infiltration of immune cells into the kidney. IL-17A concentrations were measured by ELISA in sera collected from MRL/lpr Fli-1-heterozygotes (Fli-1+/−) and MRL/lpr Fli-1+/+ control littermates. Expression of IL-17A and related proinflammatory mediators was measured by real-time polymerase chain reaction (RT-PCR). Immunofluorescence staining was performed on renal tissue from MRL/lpr Fli-1+/− and control littermates using anti-CD3, anti-CD4, and anti-IL-17A antibodies to detect Th17 cells and anti-CCL20 and anti-CD11b antibodies to identify CCL20+ monocytes. The expression of IL-17A in renal tissue was significantly reduced; this was accompanied by decreases in expression of IL-6, signal transducer and activator of transcription 3 (STAT3), and IL-1β. Likewise, we detected fewer CD3+IL-17+ and CD4+IL-17+ cells in renal tissue of MLR/lpr Fli-1+/− mice and significantly fewer CCL20+CD11b+ monocytes. In conclusion, partial deletion of Fli-1 has a profound impact on IL-17A expression and on renal histopathology in the MRL/lpr mouse.

[1]  Chrong-Reen Wang,et al.  Upregulated expression of STAT3/IL-17 in patients with systemic lupus erythematosus , 2019, Clinical Rheumatology.

[2]  M. Kashgarian,et al.  Interstitial inflammation and interstitial fibrosis and tubular atrophy predict renal survival in lupus nephritis , 2017, Clinical kidney journal.

[3]  G. Tsokos,et al.  T cells and IL-17 in lupus nephritis. , 2017, Clinical immunology.

[4]  J. Nossent,et al.  IL-17A levels in systemic lupus erythematosus associated with inflammatory markers and lower rates of malignancy and heart damage: Evidence for a dual role. , 2017, European journal of rheumatology.

[5]  N. Lou,et al.  The Fli‐1 transcription factor is a critical regulator for controlling the expression of chemokine C‐X‐C motif ligand 2 (CXCL2) , 2017, Molecular immunology.

[6]  P. Gregersen,et al.  Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection , 2016, Lupus Science & Medicine.

[7]  G. Gilkeson,et al.  Acetylation impacts Fli‐1‐driven regulation of granulocyte colony stimulating factor , 2016, European journal of immunology.

[8]  R. Drake,et al.  FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain , 2015, The Journal of Immunology.

[9]  I. Gunnarsson,et al.  IL-17 and IL-23 in lupus nephritis - association to histopathology and response to treatment , 2015, BMC Immunology.

[10]  U. Panzer,et al.  Function of the Th17/Interleukin‐17A Immune Response in Murine Lupus Nephritis , 2015, Arthritis & rheumatology.

[11]  G. Gilkeson,et al.  A Critical Role of the Transcription Factor Fli‐1 in Murine Lupus Development by Regulation of Interleukin‐6 Expression , 2014, Arthritis & rheumatology.

[12]  Eiji Suzuki,et al.  The Fli-1 Transcription Factor Regulates the Expression of CCL5/RANTES , 2014, The Journal of Immunology.

[13]  F. Shi,et al.  IL-17 Promotes Murine Lupus , 2014, The Journal of Immunology.

[14]  S. Sato,et al.  The Friend leukaemia virus integration 1 (Fli‐1) transcription factor affects lupus nephritis development by regulating inflammatory cell infiltration into the kidney , 2014, Clinical and experimental immunology.

[15]  T. Syrovets,et al.  Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages. , 2013, Acta biochimica et biophysica Sinica.

[16]  G. Gilkeson,et al.  Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney. , 2012, Clinical immunology.

[17]  L. Tam,et al.  Immunopathological Roles of Cytokines, Chemokines, Signaling Molecules, and Pattern-Recognition Receptors in Systemic Lupus Erythematosus , 2012, Clinical & developmental immunology.

[18]  G. Gilkeson,et al.  Impact of Fli‐1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice , 2010, Clinical and experimental immunology.

[19]  U. Panzer,et al.  CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis. , 2010, Journal of the American Society of Nephrology : JASN.

[20]  Gang Wang,et al.  The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. , 2009, Rheumatology.

[21]  U. Panzer,et al.  CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis1 , 2009, The Journal of Immunology.

[22]  Andreas Radbruch,et al.  CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients. , 2009, Arthritis and rheumatism.

[23]  M. Oukka,et al.  Expanded Double Negative T Cells in Patients with Systemic Lupus Erythematosus Produce IL-17 and Infiltrate the Kidneys1 , 2008, The Journal of Immunology.

[24]  Hiromu Ito,et al.  Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model , 2007, The Journal of experimental medicine.

[25]  L. Hennighausen,et al.  Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  F. Bosman,et al.  Immunohistochemical Expression of Endothelial Markers CD31, CD34, von Willebrand Factor, and Fli-1 in Normal Human Tissues , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[27]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[28]  G. Gilkeson,et al.  Decreased Expression of the Ets Family Transcription Factor Fli-1 Markedly Prolongs Survival and Significantly Reduces Renal Disease in MRL/lpr Mice1 , 2004, The Journal of Immunology.

[29]  Tien Hsu,et al.  Ets proteins in biological control and cancer , 2004, Journal of cellular biochemistry.

[30]  W. Farrar,et al.  IL-6 induces expression of the Fli-1 proto-oncogene via STAT3. , 2002, Biochemical and biophysical research communications.

[31]  D. Watson,et al.  Hemorrhage, Impaired Hematopoiesis, and Lethality in Mouse Embryos Carrying a Targeted Disruption of the Fli1Transcription Factor , 2000, Molecular and Cellular Biology.

[32]  N. Bhat,et al.  Functional relationships among ETS gene family members. , 1997, Leukemia.

[33]  N. Bhat,et al.  Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome. , 1996, International journal of oncology.

[34]  A. Bernstein,et al.  An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes , 1995, Molecular and cellular biology.

[35]  J. Goust,et al.  Systemic lupus erythematosus. , 1976, Immunology series.