Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis

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.

Repairing Effects of Aqueous Extract of Kalanchoe pinnata (Lmk) Pers. on Lupus Nephritis Mice

“…Autoantigen-antibody complexes caused inflammation that occurred in glomerulus. 20,24 One of the autoantigens was nucleosome. Nucleosomes and anti-nucleosome antibodies have been shown to bind to the glomerular basal membrane (GBM).…”

“…A well-known lupus model, Pristaneinduced lupus, was used based on its broad severe lupus nephritis manifestations. 3,19,20 The efficacy of the KP comes from multiple compounds, but we can predict the active compounds on lupus responsible receptors, such as glucocorticoid. Moreover, this research focused on the effect of aqueous extract of KP on repairing the lupus nephritis manifestations and the potential active compounds involved.…”

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with Systemic Lupus Erythematosus in Thai population

“…The TLR9/TGF-β1/PDGF-β pathway was excessively activated in peripheral mononuclear cells isolated from LN patients [64]. Besides, the upregulation of FBN2 correlated with brosis prevalence in the spontaneous LN developed mouse model (SWR X NZB1 F1) [65].…”

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with systemic lupus erythematosus in Thai population

“…The TLR9/ TGF-β1/PDGF-β pathway was excessively activated in peripheral mononuclear cells isolated from LN patients [66]. Besides, the upregulation of FBN2 correlated with fibrosis prevalence in the spontaneous LN developed mouse model (SWR X NZB1 F1) [67]. Although the function of FBN2 in SLE is unclear, collective evidence led us to hypothesize that this variant might drive either fibrosis-associated inflammation or inflammatory induction during disease pathogenesis.…”