Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis. SLE was chemically induced into IRF7-deficient mice, and glomerulonephritis with deposits of IgG and lipogranulomas were observed after 10 mo. However, these mice failed to produce anti-dsDNA, ssDNA, ribonucleoprotein, and Sm autoantibodies. Following the chemical induction, IRF7-deficient mice expressed substantially lower levels of IFN-stimulated genes than did wild-type mice, but NF-κB target genes were equally upregulated in both strains. Therefore, the type I IFN pathway seems critical for the autoantibody production, but the NF-κB activation is sufficient for the development of glomerulonephritis in this model. Our study thus demonstrates a specific requirement for IRF7 in autoantibody production and uncovers a new layer of complexity in the pathogenesis of SLE.

Associations of gene polymorphisms in interferon‐alpha signature‐related genes with autoimmune thyroid diseases

“…[30][31][32][33] Moreover, evidence showed that genetic variants of IRF7 were associated with diverse anti-double-stranded (ds)DNA production in SLE. 34 Miyagawa et al 35 reported that serum INF-α levels were reduced in an SLE mice model with IRF7 knockout compared to the wild type, and also found that those mice were unable to produce multiple kinds of autoantibodies, which further implied the strong linkage between IRF7 and antibody formation. using a luciferase reporter assay, they proved that the risk allele of rs1131665 could lead to a twofold increase in transcriptional activity of an IFN-stimulated response element compared to that of the wild type.…”

Inflammatory monocyte-derived dendritic cells mediate autoimmunity in murine model of systemic lupus erythematosus

“…We previously reported that NF-κB pathway-dependent glomerulonephritis still occurred in Irf7 −/− mice after administration of TMPD [ 9 ]. In this study, we determined the contribution of IRF8 to the development of glomerulonephritis because IRF8 controls NF-κB pathway in addition to type I IFN pathway.…”

“…Freshly isolated peritoneal cells from WT, Irf7 −/− , or Irf8 −/− mice were grown in complete RPMI in the presence or absence of TMPD. Due to its insolubility in aqueous medium, TMPD was added as the inclusion complexes with β-cyclodextrin (β-CyD; Wako) as described previously [ 9 ]. In some experiments, single cell suspensions were prepared from inguinal lymph nodes (LNs) and spleen from three strains and cultured with or without TMPD as described above.…”

“…Paraffin-embedded tissues were sectioned and stained with hematoxylin and eosin using standard techniques. Glomerular cellularity was evaluated with H&E sections of the kidneys by counting the number of nuclei per glomerular cross-section as previously described [ 9 ].…”

“…Using a murine model of SLE induced by 2,6,10,14-tetramethylpentadecane (TMPD, pristane), we previously reported that IRF7-deficient mice developed glomerulonephritis while they failed to produce autoantibodies against ssDNA, dsDNA, Sm, and RNP [ 9 ]. We demonstrated two major disease manifestations of SLE can be molecularly uncoupled, in that IRF7/type I IFN pathway is essential for autoantibody production while the NF-κB pathway sufficiently controls the development of glomerulonephritis [ 9 ].…”