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Interferon regulatory factor 5 expression levels regulate murine lupus in a type-I interferon-independent manner

ABSTRACT: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis, if any, is not known. In this study we show that IRF5 is absolutely required for disease development in the FcgRIIB-/-Yaa and FcgRIIB-/- lupus models. In contrast to IRF5-sufficient FcgRIIB-/-Yaa mice, IRF5-deficient FcgRIIB-/-Yaa mice do not develop lupus manifestations and have a phenotype comparable to wildtype mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5-heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I interferon IFN-gamma, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgRIIB-/-Yaa mice lacking the type I interferon receptor IFNAR1. Unlike the IRF5-deficient and IRF5-heterozygous FcgRIIB-/-Yaa mice, IFNAR1-deficient FcgRIIB-/-Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgRIIB-/- mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgRIIB-/-Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I interferon production. The fact that even IRF5 heterozygous mice developed minimal disease makes IRF5 a particularly attractive therapeutic target.

ORGANISM(S): Bos taurus Escherichia coli Mus musculus Gallus gallus Homo sapiens Oryctolagus cuniculus

PROVIDER: GSE17926 | GEO | 2009/09/09

SECONDARY ACCESSION(S): PRJNA119861

REPOSITORIES: GEO

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Project description:Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis, if any, is not known. In this study we show that IRF5 is absolutely required for disease development in the FcgRIIB-/-Yaa and FcgRIIB-/- lupus models. In contrast to IRF5-sufficient FcgRIIB-/-Yaa mice, IRF5-deficient FcgRIIB-/-Yaa mice do not develop lupus manifestations and have a phenotype comparable to wildtype mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5-heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I interferon IFN-gamma, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgRIIB-/-Yaa mice lacking the type I interferon receptor IFNAR1. Unlike the IRF5-deficient and IRF5-heterozygous FcgRIIB-/-Yaa mice, IFNAR1-deficient FcgRIIB-/-Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgRIIB-/- mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgRIIB-/-Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I interferon production. The fact that even IRF5 heterozygous mice developed minimal disease makes IRF5 a particularly attractive therapeutic target. Serum samples from a total of 70 mice were run on the Utz Lab Whole Protein Autoantigen Array V1.0 (a single-color platform) in order to profile their autoantibodies against a library of autoimmune antigens. All samples were run once with no replicates. The samples consisted of the following groups: For data appearing in Figure 3D, illustrating that mice lacking IRF5 have their autoantibody levels significantly affected: R2Yaa IRF5+/+: 12 R2Yaa IRF5+/-: 11 R2Yaa IRF5-/-: 14 C57BL/6 ("WT" control): 13 Total mice (arrays) for this group: 50 For data appearing in Figure 6D, illustrating that mice lacking Ifnar1 do not have their autoantibody levels significantly affected: R2Yaa Ifnar+/+: 10 R2Yaa Ifnar-/-: 10 Total mice (arrays) for this group: 20

Project description:T cells from many patients with systemic lupus erythematosus are hypoproliferative in response to TCR ligation. This defect is mediated, at least in part, through down regulation of the TCR zeta chain. Investigation of this phenomenon in lupus-prone mice revealed that the hypoproliferative T cell phenotype apparent in BXSB males is mediated in part by the Yaa locus. The BXSB model of lupus is a recombinant inbred strain that was originally derived from a cross between a male SB/LE mouse and a female C57BL/6 mouse. BXSB is unique among lupus-prone mouse strains, in that males carry an autoimmune accelerating factor on the Y chromosome, termed Yaa, which accelerates disease onset in male BXSB mice so that fatal glomerulonephritis occurs around 6 months of age. It was recently reported that the Yaa locus is a translocation of a short stretch of genes including that encoding Toll-like receptor 7 (Tlr-7) from the X to the Y chromosome, leading to a two-fold over expression of a subset of these genes, including Tlr-7, and hypersensitivity of Yaa+ cells to TLR-7 agonists. To more fully understand the functional significance of the Yaa gene and how it plays a part in the modulation of CD4+ T cell responses, we performed microarray analysis using Affymetrix 430 2.0 arrays on spleens from B6 male B6.Yaa male samples. The analysis revealed an enhanced signature of innate immunity, including increased expression not only of Tlr7 and Tlr8, in line with reports that the Yaa locus leads to a duplication of the murine Tlr7 and Tlr8 genes , but also of Tlr2, Tlr5, Cd14, Lbp, C2, C3 and genes for several heat-shock proteins. T cells from B6.Yaa mice also displayed decreased TCR? expression. Interestingly, cell surface levels of the inhibitory molecule B7-H1 were increased on B6.Yaa B cells and monocytes/macrophages. In line with increased TLR-7 expression reported in B6.Yaa mice, the TLR-7 agonist imiquimod increased B7-H1 expression on normal B cells. Restoration of proliferation in co-cultures of B6 T cells and B6.Yaa APC with B7-H1 blocking Ab demonstrated a mechanistic contribution of B7-H1 up-regulation to Yaa-mediated APC-dependent T cell hypoproliferation. In addition, T cell hypoproliferation was induced in normal B6 T cells in vitro by the application of imiquimod. However, this defect was not mediated by B7-H1 or secreted factors but was independent of APC and mediated through direct imiquimod stimulation of T cells themselves. We postulate that excessive TLR-7 stimulation in Yaa+ mice mediates T cell hypoproliferation in part through up-regulation of B7-H1 and possibly also through direct T cell-mediated effects. Keywords: differential gene expression, RNA, spleen, C57Bl/6J, B6.SB-Yaa/J, male, wild type, Yaa Control mice: four C57Bl/6J male spleens Experimental mice: three B6.SB-Yaa/J male spleens and one pool of two B6.Yaa male spleens for the third Yaa sample (GSM236622) All mice were obtained from the Jackson Laboratories between March and December 2005. Spleen cell suspensions were prepared by teasing spleen tissue through 70 micron nylon screens and lysing red cells with ammonium chloride. All mice were 8 weeks of age at the time of the experiment. RNA was separately extracted, labeled, and hybridized from each animal.

Project description:T cells from many patients with systemic lupus erythematosus are hypoproliferative in response to TCR ligation. This defect is mediated, at least in part, through down regulation of the TCR zeta chain. Investigation of this phenomenon in lupus-prone mice revealed that the hypoproliferative T cell phenotype apparent in BXSB males is mediated in part by the Yaa locus. The BXSB model of lupus is a recombinant inbred strain that was originally derived from a cross between a male SB/LE mouse and a female C57BL/6 mouse. BXSB is unique among lupus-prone mouse strains, in that males carry an autoimmune accelerating factor on the Y chromosome, termed Yaa, which accelerates disease onset in male BXSB mice so that fatal glomerulonephritis occurs around 6 months of age. It was recently reported that the Yaa locus is a translocation of a short stretch of genes including that encoding Toll-like receptor 7 (Tlr-7) from the X to the Y chromosome, leading to a two-fold over expression of a subset of these genes, including Tlr-7, and hypersensitivity of Yaa+ cells to TLR-7 agonists. To more fully understand the functional significance of the Yaa gene and how it plays a part in the modulation of CD4+ T cell responses, we performed microarray analysis using Affymetrix 430 2.0 arrays on spleens from B6 male B6.Yaa male samples. The analysis revealed an enhanced signature of innate immunity, including increased expression not only of Tlr7 and Tlr8, in line with reports that the Yaa locus leads to a duplication of the murine Tlr7 and Tlr8 genes , but also of Tlr2, Tlr5, Cd14, Lbp, C2, C3 and genes for several heat-shock proteins. T cells from B6.Yaa mice also displayed decreased TCRζ expression. Interestingly, cell surface levels of the inhibitory molecule B7-H1 were increased on B6.Yaa B cells and monocytes/macrophages. In line with increased TLR-7 expression reported in B6.Yaa mice, the TLR-7 agonist imiquimod increased B7-H1 expression on normal B cells. Restoration of proliferation in co-cultures of B6 T cells and B6.Yaa APC with B7-H1 blocking Ab demonstrated a mechanistic contribution of B7-H1 up-regulation to Yaa-mediated APC-dependent T cell hypoproliferation. In addition, T cell hypoproliferation was induced in normal B6 T cells in vitro by the application of imiquimod. However, this defect was not mediated by B7-H1 or secreted factors but was independent of APC and mediated through direct imiquimod stimulation of T cells themselves. We postulate that excessive TLR-7 stimulation in Yaa+ mice mediates T cell hypoproliferation in part through up-regulation of B7-H1 and possibly also through direct T cell-mediated effects. Keywords: differential gene expression, RNA, spleen, C57Bl/6J, B6.SB-Yaa/J, male, wild type, Yaa

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Interferon regulatory factor 5 expression levels regulate murine lupus in a type-I interferon-independent manner

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