Cancerous inhibitor of Protein Phosphatase 2A is a novel cell-autonomous regulator governing both T-and B-cell activation in vivo
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ABSTRACT: The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-? secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma. Total RNA obtained from 4 male mutant mice was compared to 4 wild type controls.
Project description:The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-γ secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma.
Project description:The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-γ secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma.
Project description:To gain insight into the promoting effect of ultrafine particle inhalation on development and progression of allergic asthma, we selected an experimental approach involving exposure to ultrafine carbon particles (UCP) and gene expression profiling of lungs from mice with experimental, ovalbumin induced allergy. Comparative gene expression analysis was performed by hybridizing pooled cDNA samples from lavaged lungs of different groups. These results suggest that allergic sensitization may represent a susceptibility factor for effects of UCP on gene expression in the lung. In sensitized individuals UCP exposure, such as found in polluted air, thus may contribute to the development and /or aggravation of allergic asthma. Keywords: Particle Inhalation, lung, ovalbumin sensitzed and challanged, experssion profiling Lungs of groups of six non-sensitized, ovalbumin sensitized, or sensitized and ovalbumin challenged BALB/cJ mice, either subjected to particle-free or UCP containing air; two replicates including one dye swap experiment have been performed for lungs: a) non-sensitized particle free air versus sensitized and ovalbumin challenged sensitized particle free air; b) non-sensitized UCP containing air versus sensitized and ovalbumin challenged sensitized UCP containing air
Project description:Background: Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections, and a clinical trial is testing its ability to prevent asthma in at-risk children. On the other hand, we previously showed that intra-nasal administration of products from microbe-rich farm environments abrogate experimental allergic asthma. Objectives: To investigate whether direct administration of OM-85 to the airway compartment protects against experimental allergic asthma, and to identify protective cellular and molecular mechanisms activated through this natural route. Methods: BALB/cJ mice (7-8 weeks old) sensitized and challenged with Ovalbumin received OM-85 intra-nasally, and cardinal cellular and molecular asthma phenotypes were measured. Murine lung gene expression was profiled by RNA-sequencing. Results: Airway administration of OM-85 suppressed allergic asthma and altered the transcriptome profile in unfractionated lung tissue. Conclusion We provide the first demonstration that administration of a standardized bacterial lysate to the airway compartment protects from experimental allergic asthma by engaging multiple immune pathways.
Project description:The objective of the study was to present a transcriptome-wide m6A methylome profile of lung tissues in mouse model of ovalbumin(OVA)-induced acute allergic asthma.
Project description:To gain insight into the promoting effect of ultrafine particle inhalation on development and progression of allergic asthma, we selected an experimental approach involving exposure to ultrafine carbon particles (UCP) and gene expression profiling of lungs from mice with experimental, ovalbumin induced allergy. Comparative gene expression analysis was performed by hybridizing pooled cDNA samples from lavaged lungs of different groups. The results suggest that allergic sensitization may represent an susceptibility factor for effects of UCP on gene expression in the lung. In sensitized individuals UCP exposure, such as found in polluted air, thus may contribute to the development and/or aggrevation of allergic asthma. Keywords: Particle Inhalation, lung, ovalbumin sensitized and challanged, expression profling
Project description:To gain insight into the promoting effect of ultrafine particle inhalation on development and progression of allergic asthma, we selected an experimental approach involving exposure to ultrafine carbon particles (UCP) and gene expression profiling of lungs from mice with experimental, ovalbumin induced allergy. Comparative gene expression analysis was performed by hybridizing pooled cDNA samples from lavaged lungs of different groups. These results suggest that allergic sensitization may represent a susceptibility factor for effects of UCP on gene expression in the lung. In sensitized individuals UCP exposure, such as found in polluted air, thus may contribute to the development and /or aggravation of allergic asthma. Keywords: Particle Inhalation, lung, ovalbumin sensitzed and challanged, experssion profiling
Project description:Kimchi is a traditional Korean food widely recognized for its probiotic properties and potential health benefits. Several lactic acid bacteria (LAB) from Kimchi exhibit immunomodulatory properties, and their efficacy has been evaluated for various immune-related diseases. However, the mechanisms underlying the immunomodulatory effects of LAB are not yet fully understood. In this study, we demonstrated the immunomodulatory effects of Latilactobacillus sakei Wikim0185, isolated from sweet potato Kimchi, in an ovalbumin (OVA)-induced allergic asthma mouse model by inducing tolerogenic dendritic cells (DCs) and regulatory T cells (Tregs). Bone marrow-derived dendritic cells (BMDCs) and OVA-peptide-stimulated splenocytes isolated from OT-II mice co-cultured with Wikim0185 exhibited increased secretion of the anti-inflammatory cytokine IL-10. Oral administration of Wikim0185 in allergic asthma experimental mice alleviated symptoms, including airway hyperresponsiveness (AHR), leukocyte infiltration, and reduced Th2-type cytokine levels in bronchoalveolar lavage (BAL) fluid. Notably, Wikim0185-treated mice displayed an increased proportion of Foxp3+ Tregs in mediastinal lymph nodes. Additionally, mediastinal lymph node cells restimulated with OVA exhibited decreased secretion of Th2-type cytokines while showing increased IL-10 production. Interestingly, RNA sequencing and chromatin immunoprecipitation (ChIP)-qPCR analysis revealed that Wikim0185 induced tolerogenic DCs through epigenetic histone modifications, increasing active chromatin marks (H3K4me3, H3K9ac, and H3K27ac) on the promoter regions of tolerogenic marker genes (Pdl1, Il10, Socs1, and Socs3). These findings suggest that Wikim0185 modulates immune responses by epigenetically reprogramming DCs, thereby promoting Treg differentiation and suppressing excessive Th2 immune responses in an allergic asthma mouse model.
Project description:This study investigated the antiallergic effects of Chamaecrista nomame extract (CN) and its isolated compound luteolin in a mouse model of ovalbumin (OVA)-induced asthma. We aimed to identify active substances within CN, elucidate their molecular signaling mechanisms, and assess their therapeutic potential for treating allergic asthma.
Project description:N6-methyladenosine (m6A), the most abundant RNA modification, plays the essential role in the immune disorders. Yet, the role of m6A and its master regulator, methyltransferase-like 3 (METTL3) in asthma remain ambiguous. Here, we found that macrophage deficient in METTL3 aggravates the ovalbumin/lipopolysaccharide (OVA/LPS)-induced neutrophilic asthma. Subsequently, we observed that METTL3 deficiency facilitates NLRP3 but not AIM2 and NLRC4-dependent inflammasome activation and IL-1β secretion. Mechanistically, METTL3 deficiency enhanced NLRP3 inflammasome activation were dependent on upregulation of ZBP1 and TRAF1. Lastly, we elucidated that METTL3 negatively regulates ZBP1 expression through m6A modification dependence. In summary, the study unveils the function of m6A in regulating NLRP3 inflammasome activation in macrophage and identifies potential targets in therapeutic intervention of neutrophilic asthma.