Molecular mechanisms of the impact of Fli-1 on lupus Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by arthritis, vasculitis, immune complex glomerulonephritis and infiltration of inflammation cells into the glomeruli. Pathogenesis of SLE is not fully understood although much progress has been made. Renal disease is the major cause of morbidity and mortality. Previous studies indicate that overexpression of transcriptional factor Fli-1 plays an important role in disease development in murine models of lupus and likely in human SLE. Two to three-fold transgenic overexpression of Fli-1 in normal mice results in the development of a lupus-like disease. Active lupus patients have higher Fli-1 mRNA in peripheral lymphocytes compared with normal controls. We have found that genetic reduction of Fli-1 expression in both MRL/lpr mice and NZM2410 mice, murine lupus models, significantly prolonged survival, decreased autoantibody production, and decreased renal pathologic proliferative changes. Our hypothesis based on our preliminary data is that Fli-1 play a critical role in inflammatory cytokine and chemokine production in kidney and activation of Toll-like receptors (TLRs) in the progression of lupus glomerulonephritis. We propose here to further defining the molecular mechanisms of the impact of Fli-1 on lupus disease development. The following specific aims are proposed to address this hypothesis:
Aim 1. Determine the role of Fli-1 in chemokine-driven leukocyte recruitment and activation during renal disease development.
Aim 2. Define the role of Fli-1 in TLR path way and kidney injury.
Aim 3. Determine the molecular mechanism whereby Fli-1 affects glomerulonephritis. These novel studies of the impact of Fli-1 on murine lupus will likely identify new pathways of disease pathogenesis applicable to human lupus and hold promise for the development of new therapeutic agents.
SLE is a chronic inflammatory disease and is considered the prototypic autoimmune disease. Renal disease is the major cause of morbidity and mortality in SLE. Our preliminary data provide clear evidence that Fli-1 expression plays a key role in murine SLE. The most striking finding is the effect on mortality when Fli-1 expression is reduced. Thus, Fli-1 has a profound effect on key factors that lead to mortality in MRL/lpr mice and NZM2410 mice along with reduced renal disease. There is already published evidence suggesting a role for Fli-1 in human lupus. This project is novel in that by studying Fli-1 effects, we believe we will discover previously unappreciated key pathways for end- organ damage and mortality in murine lupus. This proposal will lead to a better understanding of the mechanisms of disease development and perhaps provide novel strategies for the treatment of disease.
|Lou, Ning; Lennard Richard, Mara L; Yu, Jin et al. (2017) The Fli-1 transcription factor is a critical regulator for controlling the expression of chemokine C-X-C motif ligand 2 (CXCL2). Mol Immunol 81:59-66|
|Lennard Richard, Mara L; Brandon, Danielle; Lou, Ning et al. (2016) Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor. Eur J Immunol 46:2322-2332|
|Lennard Richard, Mara L; Nowling, Tamara K; Brandon, Danielle et al. (2015) Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation. Mol Immunol 63:566-73|
|Lennard Richard, Mara L; Sato, Shuzo; Suzuki, Eiji et al. (2014) The Fli-1 transcription factor regulates the expression of CCL5/RANTES. J Immunol 193:2661-8|
|Sato, Shuzo; Lennard Richard, Mara; Brandon, Danielle et al. (2014) A critical role of the transcription factor fli-1 in murine lupus development by regulation of interleukin-6 expression. Arthritis Rheumatol 66:3436-44|
|Sato, S; Zhang, X K (2014) The Friend leukaemia virus integration 1 (Fli-1) transcription factor affects lupus nephritis development by regulating inflammatory cell infiltration into the kidney. Clin Exp Immunol 177:102-9|
|Suzuki, Eiji; Williams, Sarah; Sato, Shuzo et al. (2013) The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice. Immunology 139:318-27|
|Suzuki, Eiji; Karam, Eva; Williams, Sarah et al. (2012) Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney. Clin Immunol 145:201-8|
|Moussa, Omar; LaRue, Amanda C; Abangan Jr, Romeo S et al. (2010) Thrombocytopenia in mice lacking the carboxy-terminal regulatory domain of the Ets transcription factor Fli1. Mol Cell Biol 30:5194-206|
|Molano, I; Mathenia, J; Ruiz, P et al. (2010) Decreased expression of Fli-1 in bone marrow-derived haematopoietic cells significantly affects disease development in Murphy Roths Large/lymphoproliferation (MRL/lpr) mice. Clin Exp Immunol 160:275-82|
Showing the most recent 10 out of 11 publications