Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA119861 | ENA |
REPOSITORIES: ENA
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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
2009-09-09 | E-GEOD-17926 | biostudies-arrayexpress
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.
2009-09-09 | GSE17926 | GEO
Project description:This study used the NZM2328 spontaneous murine model of lupus, iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice to examine transcription changes in murine skin after acute and chronic dosing of UVB.
2024-09-03 | GSE275384 | GEO
Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. For microarray experiments gene expression profiles of total splenic cells from two wt and Siglec-H ko mice 26 weeks after infection with luciferase expressing murine Cytomegalovirus (5x105 pfu) or from two uninfected wt and Siglec-H ko control mice were analyzed
2016-03-16 | E-GEOD-79248 | biostudies-arrayexpress
Project description:We report the response of murine hepatic macrophages to chronic CCl4 administration in wild-type mice and mice with a myeloid-specific deletion of interferon regulatory factor 5
2017-08-24 | GSE82157 | GEO
Project description:Type I interferons are critical anti-viral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The secretion of type I interferon of pDCs is modulated by Siglec-H, a DAP12 associated receptor on pDCs. We showed that Siglec-H deficient pDCs produce more of the type I interferon IFN-α in vitro and that Siglec-H ko mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo, leading to efficient clearance of the virus. Furthermore, ageing Siglec-H ko mice showed a mild form of systemic autoimmunity. In contrast, Siglec-H ko mice developed a severe form of systemic lupus-like autoimmune disease with strong kidney nephritis several weeks after a single mCMV infection. This induction of systemic autoimmune disease after virus infection in Siglec-H ko mice was accompanied by a type I interferon signature and fully dependent on type I interferon signaling. These results show that Siglec-H normally serves as modulator of type I interferon responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.
2016-03-16 | GSE79248 | GEO
Project description:Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Studies to date suggest that non-lesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA-sequencing and spatial-seq. We demonstrate that normal-appearing skin of lupus patients represents a type I interferon-rich, ‘prelesional’ environment that skews gene transcription in all major skin cell types and dramatically distorts cell-cell communication. Further, we show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining pro-inflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and non-lesional skin in lupus and identify a role for skin education of CD16+ dendritic cells in CLE pathogenesis.
2022-03-25 | GSE186476 | GEO
Project description:Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.
2023-07-06 | GSE236320 | GEO
Project description:Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.
2023-07-06 | GSE236319 | GEO
Project description:Percentages of ARID3a-expressing low density neutrophils in SLE patients correlate with lupus disease activity and Type I IFN production. ARID3a protein levels also correlate with interferon expression in plasmacytoid dendritic cells. Gene profiles mechanistically link ARID3a with inflammatory pathway regulation.
2018-09-26 | GSE117836 | GEO