Background Lupus nephritis is a serious manifestation of lupus for which treatment is only partially effective. It is characterised by the deposition of immune complexes in the kidney, activation of the complement cascade, cellular injury with the release of necrotic cell debris and the development of glomerular inflammation. However, the signalling pathways leading to the glomerular inflammation are incompletely defined. Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated in human genetic studies with an increased risk of developing lupus and, in mouse models, IRF5 has been shown to play an important role in the early phases of lupus pathogenesis including B cell autoantibody production and T cell activation by dendritic cells. IRF5 is a transcription factor that acts downstream of Toll-like receptors (TLRs) and other innate immune receptors to induce inflammatory responses. As necrotic cell debris has the potential to activate innate immune receptors, we hypothesised that IRF5 may also play a role in the later phases of lupus pathogenesis by promoting glomerular inflammation and lupus nephritis.
Materials and methods We developed a novel model of immune complex-mediated glomerulonephritis in which glomerulonephritis can be induced without exogenous adjuvant, making it possible to study the role of innate immune system activation by endogenous ligands. We induced nephritis using an endotoxin-free IgG1 fraction of sheep nephrotoxic serum (NTS) administered intravenously to wildtype (WT), IRF5-deficient (IRF5-/-) and TLR7-deficient (TLR7-/-) Fc gamma receptor IIB-deficient mice. Five days later, we euthanized the mice and measured nephritis severity.
Results WT mice developed severe glomerulonephritis characterised by glomerular necrosis and crescents in 28 ± 6% of glomeruli and a marked mononuclear cell infiltrate. IRF5-/- mice developed significantly less severe disease with glomerular crescents and necrosis seen in only 6 ± 2% of glomeruli (p < 0.01) and a substantial reduction in mononuclear cell infiltration. TLR7-/-mice exhibited an intermediate phenotype. All mice had similar amounts of IgG and complement deposition in the kidney indicating that the differences in disease severity observed were not due to differences in the initial deposition of IgG1 NTS.
Conclusions IRF5 signalling plays an important role in the pathogenesis of the effector phase of immune complex-induced glomerulonephritis. This is likely mediated, at least in part, by the role of IRF5 downstream of innate immune receptors involved in the sensing of endogenous ligands released from injured cells. The reduction in disease in TLR7-/- mice suggests that RNA may be one such endogenous ligand involved.
Acknowledgements We thank Dr. David Salant for providing the sheep nephrotoxic serum.
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