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

• Published in: PloS one Vol. 11; no. 10; p. e0164423
• Main Authors: Gardet, Agnes, Chou, Wei C, Reynolds, Taylor L, Velez, Diana B, Fu, Kai, Czerkowicz, Julia M, Bajko, Jeffrey, Ranger, Ann M, Allaire, Normand, Kerns, Hannah M, Ryan, Sarah, Legault, Holly M, Dunstan, Robert W, Lafyatis, Robert, Lukashev, Matvey, Viney, Joanne L, Browning, Jeffrey L, Rabah, Dania
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.10.2016; Public Library of Science (PLoS)
• Subjects: Adenoviruses; Analysis; Animal models; Animals; Apoptosis; Arthritis; Autoantibodies; Autoantibodies - biosynthesis; Autoimmune diseases; Autoimmunity; Biological response modifiers; Biology and Life Sciences; Disease Models, Animal; Disease Progression; DNA-Binding Proteins - metabolism; Female; Females; Fibrosis; Gene expression; Glomerulonephritis - chemically induced; Glomerulonephritis - complications; Humans; Hypergammaglobulinemia - chemically induced; Hypergammaglobulinemia - complications; Inflammation; Inflammation - chemically induced; Inflammation - complications; Interferon; Kidney Tubules - drug effects; Kidney Tubules - pathology; Kidneys; Lesions; Lupus; Lupus nephritis; Lupus Nephritis - complications; Lupus Nephritis - immunology; Lupus Nephritis - metabolism; Lupus Nephritis - pathology; Lymphocytes T; Medicine and Health Sciences; Membrane Proteins - metabolism; Mice; Nephritis; Pathogenesis; Pristane; Protein biosynthesis; Protein synthesis; Proteinuria; Research and Analysis Methods; Rodents; Signatures; Terpenes - pharmacology; Transcription, Genetic - drug effects; Up-Regulation - drug effects; Urine; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0164423

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.