Abstract
Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease.
Highlights
Lupus nephritis (LN) is a heterogeneous disease that presents with a broad spectrum of clinical and pathologic manifestations
In the SNF1 mice, onset of proteinuria was observed at 7 weeks post- pristane injection, while it occurred at 13 weeks after pristane injection in the IFNα treated NZB X NZW F1 mice (BWF1) strain as previously reported [10] (S2 Fig)
While pristane treatment in BWF1 mice has been previously shown to accelerate disease, we prioritized the characterization of pristane treatment in the SNF1 background as it led to faster disease acceleration
Summary
Lupus nephritis (LN) is a heterogeneous disease that presents with a broad spectrum of clinical and pathologic manifestations. Immune complex mediated glomerulonephritis is the most common type of renal disease, tubulointerstitial inflammation and fibrosis are important components of LN [1,2]. Several spontaneous murine models of LN exist, including BWF1 (NZB X NZW F1), SNF1 (SWR X NZB F1), MRL/lpr, in addition to congenic mouse models and many strains of gene targeted mice that present with features of LN [3]. In addition to the multitude of pathogenic mechanisms that could impact disease development, the significant time period required to develop disease in SLE prone mice poses an important hurdle to the pre-clinical modeling of lupus. Considerable effort has been devoted to establish accelerated mouse models of SLE that are relevant to human disease
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