Project description:We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.
Project description:The purpose of this study was to study the roles of GSDMD in systemic lupus erythematous. Here, we used RNA sequencing from wild type, Pristane induced wild type and Pristane induced GSDMD knockout mice to detect changes in transcriptomes of kidneys.
Project description:We characterized the longitudinal gene expression profiles of whole blood from a novel lupus model nephritis: SNF1 (SWR X NZB F1) mice treated with pristane. Genes from interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures were differentially expressed in the pristane-SNF1 model compared to the untreated matched control animals.
Project description:Low capacity to produce reactive oxygen species (ROS) due to mutations in neutrophil cytosolic factor 1 (NCF1/p47phox) is strongly associated with lupus development both in humans and mouse models. Here, we aim to identify the major mechanisms of the Ncf1-disease association. We found that plasmacytoid dendritic cells (pDCs), the most potent producers of type I IFNs, exacerbate pristane-induced lupus in ROS-defective Ncf1-mutant and human NCF1-339 variant carrying mice. ROS deficiency in mouse models with Ncf1 mutation or human NCF1-339 variant leads to enhanced pDC generation via the TLR7/AKT/mTOR pathway and accumulation at sites of inflammation, resulting in an increased IFNα secretion. The produced IFNα further stimulates the JAK1/STAT1 pathway, which we found is hyperreactive in ROS-deficient pDCs. This, in turn, leads to increased type I IFN signature and enhanced proinflammatory responses. Our discoveries explain the causative effect of dysfunctional Ncf1 and pathogenicity of pDCs in lupus.
Project description:We characterized the longitudinal gene expression profiles of kidneys from a novel lupus model nephritis: SNF1 (SWR X NZB F1) mice treated with pristane. Genes from biological processes such as IFN response, complement, Fc gamma receptors, immune recruitment, innate immune pattern recognition, antibody response and fibrosis,were upregulated in diseased kidneys.
Project description:Extracellular vesicles (EVs) are present in all body fluids. Shed by cells, their molecular make-up reflects that of their cell of origin and/or tissue pathological situation. Our working hypothesis was that analyzing the protein composition, protein abundance, and functional clustering of EVs released by peritoneal exudate cells (PECs) in the pristane experimental lupus model would allow us to identify predictive or diagnostic biomarkers that might discriminate the autoimmunity process in lupus from inflammatory reactions and/or normal physiological processes. Three pools of PE-EVs were isolated from pristane-treated mice (WT versus Cd38-/- mice) by qEV size exclusion column methodology (F5-12, F5-10 and F11-12). Protein extracts were analyzed by LC-MS/MS. Protein identification was performed with ProteinScape, and MASCOT data searching using Swiss-Prot database. For relative quantification the emPAI-based method was used. The functional enrichment analysis was based on the latest publicly available data from multiple annotation and ontology resources that can be automatically accessed through ClueGO + CluePedia apps within Cytoscape environment. STRING app and EnrichR tools were also used. Gene Ontology (GO) and signaling pathways enrichment analyses of F5-10 and F11-12 PE-EVs via ClueGO analyses showed that the proteins clustered in functionally distinct GO terms and signaling pathways. Moreover, the predominance of given GO terms in PE-EVs seemed to vary with the extent of the inflammatory/autoimmune reaction to pristane. Compared with the protein content and protein abundance in PECs (mainly Ly6Chi inflammatory monocytes and neutrophils), PE-EVs showed an enrichment in neutrophil-associated functions, in particular in PE-EVs from Cd38-/- mice.
Project description:Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.
Project description:Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. Diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.
Project description:Comparison of gene expression in inguinal lymph nodes in four groups of rats; one with induced arthritis by injection with pristane, one injected with phytol, one injected with both pristane and phytol, and one untreated group. The objective was to obtain a molecular understanding of the protective effects of phytol on pristane induced arthritis (PIA). The animals were sacrificed close to disease onset, i.e. ten days after administration.
