Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Abstract

To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1 -/-genotype mice were bred onto the MRL/lpJfas lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1 -/-mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-a when stimulated with LPS + IFN-c. IRF-1 -/-mice showed less aggravated dermatitis compared to the wild-type mice. Anti-doublestranded DNA production and proteinuria were significantly decreased in IRF-1 -/-mice compared to IRF-1 +/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1 -/-mice at 26 wk of age compared to the IRF-1 +/+ mice. Splenic CD4 -CD8 -CD44 + T cells were decreased while CD4 + CD25 + T cells were increased in the IRF-1 -/-mice when compared to IRF-1 +/+ mice. Survival rates (ED 50 ) were 22 wk for IRF-1 +/+ mice and 45 wk for IRF-1 -/-mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice. IntroductionThe etiology of systemic lupus erythematosus remains an enigma although genetic factors influenced by environmental agents appear to trigger the disease. Clearly, B cells, T cells, and macrophages play important roles in the development of lupus pathology [1][2][3].Chronic expression of Th1 cytokines secreted by Th cells is particularly harmful due to their influence on the initiation and promotion of tissue destruction [4,5]. Cytokines, including IFN-c, promote inflammation and provide a positive amplification loop responsible for escalating autoimmune kidney damage [6].MRL/lpr mice develop glomerulonephritis and vasculitis at an early age (4-5 months) [7]. Renal disease is characterized by the early influx of activated T cells and macrophages into the kidney. Activated T cells secrete IFN-c, which induces macrophages to express CSF-1, IL-1b, and TNF-a. Macrophages accumulate in the kidney during inflammation and generate IFN-a, TNF-a, and reactive oxygen species. Locally produced chemokines, particularly monocyte chemoattractant protein (MCP)-1, are also instrumental in attracting and maintaining cellular influx [8] -12 [20]. In the IRF-1 -/-NOD mouse, insulitis and diabetes were decreased accompanied by an increased survival [21]. Additional studies have suggested a role of IRF-1 and IFN-regulated genes in mediating human lupus [22][23][24]. Based on the knowledge that IRF-1 modulates inflammatory mediator production, we sought to determine whether IRF-1 gene deletion alters the severity of lupus nephritis in MRL/lpr mice. Results IRF-1 MRL/lpr mouse phenotypeTo determine the role of IRF-1 in autoimmune disease, IRF-1-knockout mice were backcrossed for eight generations to the MRL/lpr mice. After eight backcrosses, the littermates were intercrossed to yield cohorts for these studies....

Suppression of systemic autoimmunity by the innate immune adaptor STING

“…These data further highlight the contribution of NF-κB signaling downstream of STING under homeostatic conditions and point to a constitutive role of this pathway in immune regulation. It is possible that other transcription factors, such as IRFs and STATs, may be engaged downstream of STING, but likely candidates IRF5, IRF1, STAT1, and STAT6 have previously been shown to promote lupus pathology (38)(39)(40)(41)(42), in contrast to the suppressive role of STING documented in this study. Thus, it is unlikely that transcriptional activity of any of these factors contributes to a STING-dependent suppressive pathway.…”

IRF4 Deficiency Abrogates Lupus Nephritis Despite Enhancing Systemic Cytokine Production

“…IRF1 acts as a nonredundant transcription factor that promotes the expression of many proinflammatory genes in immune and nonimmune cells. 8,9 IRF3 and IRF7 mediate the expression of type I IFNs upon activation of innate viral nucleic acid sensors that, in lupus, can also be activated by endogenous nucleic acids and lupus autoantigens. 7,12 IRF5 is required for immune cell maturation and for TLR signaling, two mechanisms that contribute to human SLE and lupus nephritis of Fc␥RIIBϪ/ϪYaa or Fc␥RIIBϪ/Ϫ mice.…”

“…IRF-1 is a proinflammatory transcription factor that triggers the expression of proinflammatory cytokines in tubular epithelial cells and immune cells in the postischemic kidney 8 as well as in mesangial cells during lupus nephritis of MRL-(Fas)lpr mice. 9 IRF3 and IRF7 mediate type I IFN production upon immune recognition of viral and endogenous nucleic acids in DCs, 10 including TLR7 signaling, which was shown to be an essential pathway in SLE. 7,[11][12][13] IRF5 is required for immune cell maturation and for TLR signaling, two mechanisms that contribute to SLE and lupus nephritis of Fc␥RIIBϪ/ϪYaa or Fc␥RIIBϪ/Ϫ mice 14 and in lupus secondary to pristane injection.…”

IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

“…Both IRF7 and IRF5 are critical for DC production of IFN-α, IFN-β, and IL-6 by anti-RNP immune complexes and by conventional TLR7 and TLR9 ligands (70,71). MRL/lpr mice lacking the IRF1 gene develop less severe disease compared with WT mice (72). Finally, female mice deficient for IRF4-binding protein develop a lupus-like disease characterized by hypergammaglobulinemia, autoantibody production, and immune complex-mediated glomerulonephritis (73).…”