TLR7 Activation Accelerates Cardiovascular Pathology in a Mouse Model of Lupus.
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ABSTRACT:
SUBMITTER: Elshikha AS
PROVIDER: S-EPMC9289616 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa CD4 T cells develop the molecular signature for T(FH) cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Sles1 had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.
| S-EPMC1502563 | biostudies-literature
Project description:BackgroundMounting evidence suggests that increased gut permeability, or leaky gut, and the resulting translocation of pathobionts or their metabolites contributes to the pathogenesis of Systemic Lupus Erythematosus. However, the mechanisms underlying the induction of gut leakage remain unclear. In this study, we examined the effect of a treatment with a TLR7/8 agonist in the B6.Sle1.Sle2.Sle3 triple congenic (TC) mouse, a spontaneous mouse model of lupus without gut leakage.Materials and methodsLupus-prone mice (TC), TC.Rag1-/- mice that lack B and T cells, and congenic B6 healthy controls were treated with R848. Gut barrier integrity was assessed by measuring FITC-dextran in the serum following oral gavage. Claudin-1 and PECAM1 expression as well as the extent of CD45+ immune cells, B220+ B cells, CD3+ T cells and CD11b+ myeloid cells were measured in the ileum by immunofluorescence. NKp46+ cells were measured in the ileum and colon by immunofluorescence. Immune cells in the ileum were also analyzed by flow cytometry.ResultsR848 decreased gut barrier integrity in TC but not in congenic control B6 mice. Immunofluorescence staining of the ileum showed a reduced expression of the tight junction protein Claudin-1, endothelial cell tight junction PECAM1, as well as an increased infiltration of immune cells, including B cells and CD11b+ cells, in R848-treated TC as compared to untreated control mice. However, NKp46+ cells which play critical role in maintaining gut barrier integrity, had a lower frequency in treated TC mice. Flow cytometry showed an increased frequency of plasma cells, dendritic cells and macrophages along with a decreased frequency of NK cells in R848 treated TC mice lamina propria. In addition, we showed that the R848 treatment did not induce gut leakage in TC.Rag1-/- mice that lack mature T and B cells.ConclusionsThese results demonstrate that TLR7/8 activation induces a leaky gut in lupus-prone mice, which is mediated by adaptive immune responses. TLR7/8 activation is however not sufficient to breach gut barrier integrity in non-autoimmune mice.
| S-EPMC10358848 | biostudies-literature
Project description:The purpose of our study was to investigate the effects of the adaptor Bank1 in TLR7 signaling using the B6.Sle1.yaa mouse, a lupus model that develops disease through exacerbated TLR7 expression. Crosses of B6.Sle1.yaa with Bank1-/- mice maintained several B and myeloid cell phenotypes close to normal wild-type levels. Most striking was the reduction in total serum IgG antibodies, but not of IgM, and reduced serum levels of autoantibodies, IL-6, and BAFF. Bank1 deficiency did modify numbers of MZ B cells and total B cell numbers, as well as expression of CXCR4 by follicular helper T cells. Other T cell changes were not observed. Bank1 deficiency did not modify numbers of germinal center B cells or plasma cells or clinical disease outcomes. Purified B cells from Bank1 deficient mice had strongly reduced Ifnb, Ifna4, Irf7, Aicda and Stat1 gene expression following TLR7 agonist stimulation. Interestingly, phosphorylation of Tyr701, but not of Ser727 of STAT1, was impaired in splenic B cells from B6.Sle1.yaa.Bank1-/- mice, as was the nuclear translocation of IRF7 in response to TLR7 agonist stimulation. Further, Bank1 deficiency in B6.Sle1.yaa mice reduced the production of IgG2c after in vitro TLR7 agonist stimulation. Our results demonstrate that Bank1 controls TLR7-mediated type I interferon production. Combined with the control of the nuclear translocation of IRF7, the modulation of STAT1 transcription and phosphorylation, Bank1 contributes to IgG production during development of autoimmune disease.
| S-EPMC4882053 | biostudies-literature
Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with cognitive impairment and later dementia among the elderly. Mounting evidence shows that adverse maternal environments during the fetal development increase the risk of diseases later in life including neurological disorders, and suggests an early origin in the development of AD-related dementia (ADRD) in utero. In the present study, we investigated the impact of antenatal hypoxia and fetal stress on the initiation of AD-related pathology in offspring of 5xFAD mice. We showed that fetal hypoxia significantly reduced brain and body weight in the fetal and the early postnatal period, which recovered in young adult mice. Using spontaneous Y-maze, novel object recognition (NOR), and open field (OF) tasks, we found that antenatal hypoxia exacerbated cognitive decline in offspring of 5xFAD compared with normoxia control. Of interest, fetal hypoxia did not alter intraneuronal soluble amyloid-β (Aβ) oligomer accumulation in the cortex and hippocampus in 5xFAD mouse offspring, indicating that antenatal hypoxia increased the vulnerability of the brain to synaptotoxic Aβ in the disease onset later in life. Consistent with the early occurrence of cognitive decline, we found synapse loss but not neuronal death in the cerebral cortex in 5xFAD but not wild-type (WT) offspring exposed to antenatal hypoxia. Furthermore, we also demonstrated that antenatal hypoxia significantly increased microglial number and activation, and reactive astrogliosis in the cerebral cortex in WT offspring. Moreover, antenatal hypoxia resulted in an exacerbated increase of microgliosis and astrogliosis in the early stage of AD in 5xFAD offspring. Together, our study reveals a causative link between fetal stress and the accelerated onset of AD-related pathology, and provides mechanistic insights into the developmental origin of aging-related neurodegenerative disorders.
| S-EPMC7472639 | biostudies-literature
Project description:Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes.
| S-EPMC6967132 | biostudies-literature
Project description:BackgroundPatients with systemic lupus erythematosus (SLE), an autoimmune disease, have a higher risk of cardiovascular (CV) disease and death. In addition, up to 40%-50% of SLE patients develop lupus nephritis (LN) and chronic kidney disease, which is an additional CV risk factor. Thus, the individual contributions of LN and other SLE-specific factors to CV events are unclear.MethodsIn this study, we investigated the effect of LN on the development of CV changes using the female NZBxNZW F1 (NZB/W) mouse model of lupus-like disease, with female NZW mice as controls. Standard serologic, morphologic, immunohistologic, and molecular analyses were performed. In a separate group of NZB/W mice, systolic blood pressure (BP) was measured during the course of the disease using tail plethysmography.ResultsOur data show marked CV changes in NZB/W mice, i.e., increased heart weight, hypertrophy of the left ventricle (LV) and septum, and increased wall thickness of the intramyocardial arteries and the aorta, which correlated with the progression of renal damage, but not with the age of the mice. In addition, systolic BP was increased in NZB/W mice only when kidney damage progressed and proteinuria was present. Pathway analysis based on gene expression data revealed a significant upregulation of the response to interferon beta in NZB/W mice with moderate kidney injury compared with NZB mice. Furthermore, IFI202b and IL-6 mRNA expression is correlated with CV changes. Multiple linear regression analysis demonstrated serum urea as a surrogate marker of kidney function and IFI202b expression as an independent predictor for LV wall thickness. In addition, deposition of complement factors CFD and C3c in hearts from NZB/W mice was seen, which correlated with the severity of kidney disease.ConclusionsThus, we postulate that the pathogenesis of CV disease in SLE is affected by renal impairment, i.e., LN, but it can also be partly influenced by lupus-specific cardiac expression of pro-inflammatory factors and complement deposition.
| S-EPMC10405627 | biostudies-literature
Project description:Lupus nephritis with pronounced signs of chronic kidney disease leads to significant changes in the heart. It is not yet clear whether these changes are caused by the chronic kidney disease or by the autoimmune disease. It is also unclear which factors are responsible for the cardiovascular changes. Therefore, the gene expression of mice with lupus nephritis (NZB_W) will be compared with healthy controls (NZW).
2024-02-16 | GSE226308 | GEO
Project description:Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that MyD88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which MyD88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, T-bet+ B cells were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of T-bet-expressing B cells in pSS.
| S-EPMC9799719 | biostudies-literature
Project description:Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770-3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7- and myeloid differentiation factor 88 (MyD88)-dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fcgamma receptors (FcgammaRs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by FcgammaRs.
| S-EPMC2605237 | biostudies-literature
Project description:Mitochondrial dysfunction and oxidative stress are involved in Alzheimer disease (AD) pathogenesis. In human AD brains, the activity of the alpha-ketoglutarate dehydrogenase enzyme complex (alpha-KGDHC) is reduced. KGDHC is mostly involved in NADH production. It can also participate in oxidative stress and reactive oxygen species (ROS) production. The mitochondrial dihydrolipoyl succinyltransferase enzyme (DLST) is a key subunit specific to the alpha-KGDHC. In cultured cells, reduction of DLST increased H(2)O(2)-induced ROS generation and cell death. Thus, we asked whether partial genetic deletion of DLST could accelerate the onset of AD pathogenesis, using a transgenic mouse model of amyloid deposition crossed with DLST(+/-) mice. Tg19959 mice, which carry the human amyloid precursor protein with two mutations, develop amyloid deposits and progressive behavioral abnormalities. We compared Tg19959 mice to Tg19959-DLST(+/-) littermates at 2-3 months of age and studied the effects of DLST deficiency on amyloid deposition, spatial learning and memory, and oxidative stress. We found that alpha-KGDHC activity was reduced in DLST(+/-) mice. We also found that DLST deficiency increased amyloid plaque burden, Abeta oligomers, and nitrotyrosine levels and accelerated the occurrence of spatial learning and memory deficits in female Tg19959 mice. Our data suggest that alpha-KGDHC may be involved in AD pathogenesis through increased mitochondrial oxidative stress.
| S-EPMC2761144 | biostudies-literature