Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease.
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ABSTRACT:
SUBMITTER: Ban T
PROVIDER: S-EPMC8290003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The transcription factor IFN regulatory factor 5 (IRF5) is a central mediator of innate and adaptive immunity. Genetic variations within IRF5 are associated with a risk of systemic lupus erythematosus (SLE), and mice lacking Irf5 are protected from lupus onset and severity, but how IRF5 functions in the context of SLE disease progression remains unclear. Using the NZB/W F1 model of murine lupus, we show that murine IRF5 becomes hyperactivated before clinical onset. In patients with SLE, IRF5 hyperactivation correlated with dsDNA titers. To test whether IRF5 hyperactivation is a targetable function, we developed inhibitors that are cell permeable, nontoxic, and selectively bind to the inactive IRF5 monomer. Preclinical treatment of NZB/W F1 mice with an inhibitor attenuated lupus pathology by reducing serum antinuclear autoantibodies, dsDNA titers, and the number of circulating plasma cells, which alleviated kidney pathology and improved survival. Clinical treatment of MRL/lpr and pristane-induced lupus mice with an inhibitor led to significant reductions in dsDNA levels and improved survival. In ex vivo human studies, the inhibitor blocked SLE serum-induced IRF5 activation and reversed basal IRF5 hyperactivation in SLE immune cells. We believe this study provides the first in vivo clinical support for treating patients with SLE with an IRF5 inhibitor.
| S-EPMC7685739 | biostudies-literature
Project description:The IRF5-SLE risk haplotype is associated with SLE disease severity. We hypothesized that neutrophils from healthy risk donors would carry a pathogenic gene signature compared to non-risk donors. To compare basal neutrophil gene signature between risk and non-risk healthy individuals, fresh whole blood was collected from healthy donors, and granulocytes were extracted from the remaining pellet following Ficoll purification. RNA-seq libraries were prepared from globin-reduced RNA extracted from the granulocytes using the Qiagen RNA preparation kit.
2020-04-07 | GSE137067 | GEO
Project description:BackgroundThis study aimed to investigate fetal and maternal outcomes in women with active lupus nephritis (LN). Specifically, we compared women who had new-onset LN and those with pre-existing LN during pregnancy.MethodsPatients with active LN during pregnancy were divided into the new-onset group (LN first occurred during pregnancy) and the pre-existing group (a history of LN) on the basis of the onset time of LN. Data on clinical features, laboratory findings, and pregnancy outcome were collected and analyzed between the two groups. Multivariate logistic regression analysis was used to compare the effects of active LN on adverse pregnancy outcomes.ResultsWe studied 73 pregnancies in 69 women between 2010 and 2019. Of these, 38 pregnancies were in the pre-existing LN group and 35 were in the new-onset group. Patients with pre-existing LN had a higher risk of composite adverse fetal outcomes than those with new-onset LN [adjusted odds ratio (ORs), 44.59; 95% confidence interval (CI), 1.21-1664.82; P = 0.039]. However, the two groups had similar adverse maternal outcomes (ORs, 1.24; 95% CI, 0.36-4.29). Serum albumin and proteinuria significantly improved after pregnancy (P < 0.001). Kaplan-Meier analysis showed that the long-term renal outcome was similar between the two groups.ConclusionsPregnant patients with pre-existing LN were associated with a higher risk of composite adverse fetal outcomes than those with new-onset LN. However, these two groups of patients had similar adverse maternal outcomes. The long-term renal outcomes were not different after pregnancy between these two groups.
| S-EPMC8691084 | biostudies-literature
Project description:BackgroundThe molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic.MethodsWe tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours.ResultsSystemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol.ConclusionsThe Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer.
| S-EPMC3049604 | biostudies-literature
Project description:Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell-intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.
| S-EPMC8410043 | biostudies-literature
Project description:BackgroundRecently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene.AimTo test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA.Patients and methods100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE.ResultsThe analysis showed the absence of linkage and association globally and in "autoimmune" RA subsets, with a weak non-significant trend against the IRF5 rs20046470-T allele. Given the robustness of familial-based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE.ConclusionOur results exclude the IRF5 rs2004640-T allele as a major genetic factor for RA in this French Caucasian population.
| S-EPMC1954661 | biostudies-literature
Project description:Pre-existing diabetes, hypertension and kidney disorders are prominent risk factors of pre-eclampsia (PE). It is a multifactorial pregnancy disorder associated with high blood pressure, proteinuria, and multiorgan failure, which develops after the 20th week of pregnancy. It is one of the most feared pregnancy disorders, as it consumes thousands of fetomaternal lives per annum. According to clinical and pathological studies, the placenta appears to be a key player in the pathogenesis of PE; however, the exact origin of this disorder is still under debate. Defective placentation and angiogenesis are the hallmarks of PE progression. This angiogenic imbalance, together with maternal susceptibility, might determine the severity and clinical presentation of PE. This article comprehensively examines the mechanisms of pathogenesis of PE and current evidence of the factors involved in its progression. Finally, this article will explore the genetic association of PE, various candidate genes, their proposed mechanisms and variants involved in its pathogenesis.
| S-EPMC9778778 | biostudies-literature
Project description:Genetic variants within or near the interferon regulatory factor 5 (IRF5) locus associate with systemic lupus erythematosus (SLE) across ancestral groups. The major IRF5-SLE risk haplotype is common across populations, yet immune functions for the risk haplotype are undefined. We characterized the global immune phenotype of healthy donors homozygous for the major risk and nonrisk haplotypes and identified cell lineage-specific alterations that mimic presymptomatic SLE. Contrary to previous studies in B lymphoblastoid cell lines and SLE immune cells, IRF5 genetic variants had little effect on IRF5 protein levels in healthy donors. Instead, we detected basal IRF5 hyperactivation in the myeloid compartment of risk donors that drives the SLE immune phenotype. Risk donors were anti-nuclear antibody positive with anti-Ro and -MPO specificity, had increased circulating plasma cells and plasmacytoid dendritic cells, and had enhanced spontaneous NETosis. The IRF5-SLE immune phenotype was conserved over time and probed mechanistically by ex vivo coculture, indicating that risk neutrophils are drivers of the global immune phenotype. RNA-Seq of risk neutrophils revealed increased IRF5 transcript expression, IFN pathway enrichment, and decreased expression of ROS pathway genes. Altogether, the data support that individuals carrying the IRF5-SLE risk haplotype are more susceptible to environmental/stochastic influences that trigger chronic immune activation, predisposing to the development of clinical SLE.
| S-EPMC7098722 | biostudies-literature
Project description:Recently, two studies provided convincing evidence that IFN regulatory factor 5 (IRF5) gene polymorphisms are significantly associated with systemic lupus erythematosus (SLE) in several white populations. To replicate the association with SLE in an Asian population, we examined the genetic effects in our SLE cohort from a Korean population. A total of 1,565 subjects, composed of 593 cases and 972 controls, were genotyped using the TaqMan (Applied Biosystems, Foster City, CA, USA) method. The genetic effects of polymorphisms on the risk of SLE were evaluated using chi2 tests and a Mantel-Haenszel meta-analysis. Statistical analysis revealed results in the Korean population were similar to the previous reports from white populations. The rs2004640 T allele had a higher frequency in SLE cases (0.385) than controls (0.321; odds ratio (OR) = 1.32, P = 0.0003). In combined analysis, including all seven independent cohorts from the three studies so far, robust and consistent associations of the rs2004640 T allele with SLE were observed. The estimate of risk was OR = 1.44 (range, 1.34-1.55), with an overall P = 1.85 x 10(-23) for the rs2004640 T allele. The haplotype (rs2004640T-rs2280714T) involved in both the alternative splice donor site and the elevated expression of IRF5 also had a highly significant association with SLE (pooled, P = 2.11 x 10(-16)). Our results indicate that the genetic effect on the risk of SLE mediated by IRF5 variants can be generally accepted in both white and Asian populations.
| S-EPMC1906810 | biostudies-literature
Project description:Pre-B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre-B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre-B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK(-/-) mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27(kip1) expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27(kip1) induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7-dependent proliferation and survival of pre-B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre-B-cell leukemia.
| S-EPMC2644075 | biostudies-literature