SPARC regulation of PMN clearance protects from pristane-induced lupus and rheumatoid arthritis.
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ABSTRACT:
SUBMITTER: Sangaletti S
PROVIDER: S-EPMC8188360 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTo facilitate the development of therapies for rheumatoid arthritis (RA), the Innovative Medicines Initiative BTCure has combined the experience from several laboratories worldwide to establish a series of protocols for different animal models of arthritis that reflect the pathogenesis of RA. Here, we describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data.MethodsWe optimized dose of pristane and immunization procedures and determined the effect of age, gender, and housing conditions. We further assessed cage-effects, reproducibility, and frequency of chronic arthritis, disease markers, and efficacy of standard and novel therapies.ResultsOut of 271 rats, 99.6% developed arthritis after pristane-administration. Mean values for day of onset, day of maximum arthritis severity and maximum clinical scores were 11.8±2.0 days, 20.3±5.1 days and 34.2±11 points on a 60-point scale, respectively. The mean frequency of chronic arthritis was 86% but approached 100% in long-term experiments over 110 days. Pristane was arthritogenic even at 5 microliters dose but needed to be administrated intradermally to induce robust disease with minimal variation. The development of arthritis was age-dependent but independent of gender and whether the rats were housed in conventional or barrier facilities. PIA correlated well with weight loss and acute phase reactants, and was ameliorated by etanercept, dexamethasone, cyclosporine A and fingolimod treatment.ConclusionsPIA has high incidence and excellent reproducibility. The chronic relapsing-remitting disease and limited systemic manifestations make it more suitable than adjuvant arthritis for long-term studies of joint-inflammation and screening and validation of new therapeutics.
| S-EPMC4881957 | biostudies-literature
Project description:Galectin-3 (Gal-3) controls intercellular and cell-extracellular matrix interactions during immunological responses. In chronic inflammation, Gal-3 is associated with fibrotic events, regulates B cell differentiation and delays lupus progression. Gal-3 deficient mice (Lgals3-/-) have intense germinal center formation and atypical plasma cell generation correlated to high levels IgG, IgE, and IgA. Here, we used pristane (2,6,10,14-tetramethylpentadecane) to induce lupus-like syndrome in Lgals3-/- and Lgals3+/+ BALB/c mice. Mesentery and peritoneal cells were monitored because promptly react to pristane injected in the peritoneal cavity. For the first time, mesenteric tissues have been associated to the pathogenesis of experimental lupus-like syndrome. In Lgals3+/+ pristane-induced mice, mesentery was hallmarked by intense fibrogranulomatous reaction restricted to submesothelial regions and organized niches containing macrophages and B lymphocytes and plasma cells. In contrast, Lgals3-/- pristane-treated mice had diffuse mesenteric fibrosis affecting submesothelium and peripheral tissues, atypical M1/M2 macrophage polarization and significant DLL1+ cells expansion, suggesting possible involvement of Notch/Delta pathways in the disease. Early inflammatory reaction to pristane was characterized by significant disturbances on monocyte recruitment, macrophage differentiation and dendritic cell (DC) responses in the peritoneal cavity of pristane-induced Lgals3-/- mice. A correlative analysis showed that mesenteric damages in the absence of Gal-3 were directly associated with severe portal inflammation and hepatitis. In conclusion, it has suggested that Gal-3 orchestrates histological organization in the mesentery and prevents lupoid hepatitis in experimental lupus-like syndrome by controlling macrophage polarization, Notch signaling pathways and DC differentiation in mesenteric structures.
| S-EPMC6786989 | biostudies-literature
Project description:Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn -/- mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production. In order to study the basophil-specific mechanisms by which these cells contribute to LN development, we needed to validate their involvement in a genetically independent SLE-like mouse model. Pristane, when injected to non-lupus-prone mouse strains, induces a LN-like disease. In this inducible model, basophils were activated and accumulated in SLOs to promote autoantibody production. Basophil depletion by two distinct approaches dampened LN-like disease, demonstrating their contribution to the pristane-induced LN model. These results enable further studies to decipher molecular mechanisms by which basophils contribute to lupus progression.
| S-EPMC5554199 | biostudies-literature
Project description:BackgroundPristane-treated mice chronically produce high levels of anti-ribonucleoprotein/Smith (anti-Sm/RNP) and other lupus autoantibodies. The present study addressed how these autoantibody levels are maintained over time.MethodsLupus was induced in BALB/c mice using pristane. Naïve B cells, switched memory B cells, switched plasmablasts, and plasma cells were flow-sorted and total IgG and anti-U1A (RNP) autoantibodies were determined with ELISA.ResultsB cells with a switched "memory-like" (CD19(+)CD138(-)IgM(-)IgD(-)) (sMB) phenotype were increased in pristane-treated mice and expressed higher levels of Toll like receptor 7 (Tlr7) than cells with this phenotype from untreated mice. Flow-sorted sMB cells from pristane-treated mice did not secrete IgG spontaneously, but were hyper-responsive to both synthetic (R848) and natural (apoptotic cells) TLR7 ligands, resulting in increased IgG production in vitro. The flow-sorted sMB cells also could be driven by R848 to produce IgG anti-U1A autoantibodies. Production of IgG was strongly inhibited by both JSH-23 and SB203580, suggesting that the canonical NFκB and p38 MAPK pathways, respectively, contribute to the TLR7 ligand hyper-responsiveness of sMB from pristane-treated mice.ConclusionsThe switched memory B cell subset from pristane-treated mice is expanded and shows an increased propensity to undergo terminal (plasma cell) differentiation in response to synthetic and natural TLR7 ligands. The data suggest that the decreased clearance of apoptotic cells characteristic of pristane-treated mice might help maintain high serum levels of anti-RNP/Sm autoantibodies.
| S-EPMC4718029 | biostudies-literature
Project description:The complement component C1q is known to play a controversial role in the pathogenesis of systemic lupus erythematosus, but the underlying mechanisms remain poorly understood. Intraperitoneal injection of pristane induces a lupus-like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b(+) Ly6C(high) inflammatory monocytes in a TLR7-dependent fashion. C1q was also shown to influence the secretion of IFN-α. In this study, we explored whether C1q deficiency could affect pristane-induced lupus. Surprisingly, C1qa(-/-) mice developed lower titers of circulating Abs and milder arthritis compared with the controls. In keeping with the clinical scores, 2 wk after pristane injection the peritoneal recruitment of CD11b(+) Ly6C(high) inflammatory monocytes in C1qa(-/-) mice was impaired. Furthermore, C1q-deficient pristane-primed resident peritoneal macrophages secreted significantly less CCL3, CCL2, CXCL1, and IL-6 when stimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristane-priming phase rectified this defect. Conversely, pristane-primed macrophages from C3-deficient mice did not show impaired cytokine production. These findings demonstrate that C1q deficiency impairs the TLR7-dependent chemokine production by pristane-primed peritoneal macrophages and suggest that C1q, and not C3, is involved in the handling of pristane by phagocytic cells, which is required to trigger disease in this model.
| S-EPMC4745139 | biostudies-literature
Project description:BackgroundThe roles of gut microbiota in the pathogenesis of SLE have been receiving much attention during recent years. However, it remains unknown how fecal microbiota transplantation (FMT) and microbial metabolites affect immune responses and lupus progression.MethodsWe transferred fecal microbiota from MRL/lpr (Lpr) mice and MRL/Mpj (Mpj) mice or PBS to pristane-induced lupus mice and observed disease development. We also screened gut microbiota and metabolite spectrums of pristane-induced lupus mice with FMT via 16S rRNA sequencing, metagenomic sequencing, and metabolomics, followed by correlation analysis.ResultsFMT from MRL/lpr mice promoted the pathogenesis of pristane-induced lupus and affected immune cell profiles in the intestine, particularly the plasma cells. The structure and composition of microbial communities in the gut of the FMT-Lpr mice were different from those of the FMT-Mpj mice and FMT-PBS mice. The abundances of specific microbes such as prevotella taxa were predominantly elevated in the gut microbiome of the FMT-Lpr mice, which were positively associated with functional pathways such as cyanoamino acid metabolism. Differential metabolites such as valine and L-isoleucine were identified with varied abundances among the three groups. The abundance alterations of the prevotella taxa may affect the phenotypic changes such as proteinuria levels in the pristane-induced lupus mice.ConclusionThese findings further confirm that gut microbiota play an important role in the pathogenesis of lupus. Thus, altering the gut microbiome may provide a novel way to treat lupus.
| S-EPMC10018936 | biostudies-literature
Project description:Activation of multiple inflammasomes in monocytes/macrophages is associated with the pathogenesis of systemic lupus erythematosus (SLE). Gasdermin D (GSDMD)-mediated pyroptosis, a common consequence of multiple activated inflammasomes, is a programmed cell death with strong inflammatory responses. This suggested that targeting monocyte/macrophage pyroptosis might provide an opportunity to cure SLE. Here, we aimed to investigate the effect of disulfiram (DSF), a small molecule inhibitor of pyroptosis, and its potential therapeutic mechanism for SLE. The mRNA expression of GSDMD and IL-1β were significantly increased in peripheral blood mononuclear cells (PBMCs) from SLE patients. Importantly, we found serum from SLE patients rather than healthy controls induced GSDMD-mediated pyroptosis in THP-1 cells, as evidenced by enhanced LDH release, increased number of PI-positive cells, and high expression of full-length GSDMD and N-terminal GSDMD. Interestingly, treatment with DSF obviously inhibited pyroptosis of THP-1 cells induced by serum from SLE patients. Of note, DSF administration reduced proteinuria, serum anti-dsDNA level, and renal immune complex. It also attenuated renal damage in PIL mice. Further research found that the high level of serum IL-β and GSDMD-mediated pyroptosis of glomerular macrophages in PIL mice were rescued with DSF treatment. These data implied that GSDMD-mediated monocytes/macrophages pyroptosis played an important role in the pathogenesis of SLE and DSF might be a potential alternative therapeutic agent for SLE.
| S-EPMC9440918 | biostudies-literature
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.
| S-EPMC7103630 | biostudies-literature
Project description:BackgroundSystemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by the production of autoantibodies. To date, no therapy has been found to satisfactorily treat SLE. SIRT1 deficiency results in the development of an autoimmune syndrome in mice, including a high titer of anti-nuclear antibody in serum, immunoglobulin deposition in the kidney, and immune complex glomerulonephritis. Resveratrol is an activator of SIRT1 and possesses anti-inflammation and immune-regulatory properties.ObjectiveTo evaluate the preventative effects of resveratrol on a pristane-induced lupus animal model and assess its putative immune modulation effects.MethodsBALB/c mice received a single intraperitoneal injection of 0.5 ml of pristane on day 1 and then various doses of resveratrol were given to the mice daily starting on day 2 and continuing for seven months. The autoantibodies in serum and supernatants were measured. Single cells isolated from spleen, isolated CD4+ T cells, and CD19+ B cells were cultured with or without resveratrol in vitro and assessed by flow cytometry.ResultsResveratrol attenuated proteinuria, immunoglobuin depositon in kidney, and glomerulonephritis as well as IgG1 and IgG2a in serum in pristane-induced lupus mice. Resveratrol also suppressed CD69 and CD71 expression on CD4+ T cells as well as CD4+ T cell proliferation, induced CD4+ T cell apoptosis, and decreased CD4 IFNγ+ Th1 cells and the ratio of Th1/Th2 cells in vitro. In vitro antibody production and proliferation of B cells were also inhibited.ConclusionResveratrol possesses protective effects in pristane-induced lupus mice and may represent a novel approach for the management of SLE.
| S-EPMC4263676 | biostudies-literature
Project description:Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1 -/- mice showed increased influx of Ly6Chi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1 -/- mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1 -/- mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
| S-EPMC7541920 | biostudies-literature