Eosinophil-Associated Innate IL-17 Response Promotes Aspergillus fumigatus Lung Pathology

Aspergillus fumigatus is a common widespread microorganism with environmental, biological and clinical relevance. After inhalation, swollen conidia can germinate, colonize and invade pulmonary tissues. Eosinophils have been described as key cells in A. fumigatus lung infection. However, their specific role in protecting or damaging lung tissue as well as their relatioship among different A. fumigatus strains is poorly understood. Previously, it has been reported that eosinophils are able to produce IL-17 and mediate an innate response that protected mice from infection using Af293 and CEA10 strains. Here, we have developed a set of new experiments with the CEA17-derived A1163 strain of A. fumigatus. Using ΔdblGATA1 mice, we demonstrate that eosinophils produce IL-17 and are involved in control of neutrophil, macrophage and lymphocyte recruitment. We found that eosinophils also induce high levels of cytokines and chemokines, generating an intense inflammatory process. Eosinophils are responsible for increased pulmonary dysfunction and elevated lethality rates in mice. Curiously, fungal burden was not affected. To address the role of IL-17 signaling, pharmacological inhibition of this mediator in the airways with anti-IL-17 antibody was able to reduce inflammation in the airways and protect infected mice. In conclusion, our results demonstrate that eosinophils control IL-17-mediated response and contribute to lung pathology after A. fumigatus infection. Therefore, eosinophils may represent a potential target for controlling exacerbated inflammation and prevent tissue damage during this fungal infection

Induction of Eosinophil Apoptosis by the Cyclin-Dependent Kinase Inhibitor AT7519 Promotes the Resolution of Eosinophil-Dominant Allergic Inflammation

Eosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be defective in allergic diseases. However, enhanced resolution of eosinophilic inflammation by deliberate induction of eosinophil apoptosis using pharmacological agents has not been previously demonstrated. Here we investigated the effect of a novel cyclin-dependent kinase inhibitor drug, AT7519, on human and mouse eosinophil apoptosis and examined whether it could enhance the resolution of a murine model of eosinophil-dominant inflammation in vivo.Eosinophils from blood of healthy donors were treated with AT7519 and apoptosis assessed morphologically and by flow-cytometric detection of annexin-V/propidium iodide staining. AT7519 induced eosinophil apoptosis in a concentration dependent manner. Therapeutic administration of AT7519 in eosinophil-dominant allergic inflammation was investigated using an established ovalbumin-sensitised mouse model of allergic pleurisy. Following ovalbumin challenge AT7519 was administered systemically at the peak of pleural inflammation and inflammatory cell infiltrate, apoptosis and evidence of macrophage phagocytosis of apoptotic eosinophils assessed at appropriate time points. Administration of AT7519 dramatically enhanced the resolution of allergic pleurisy via direct induction of eosinophil apoptosis without detriment to macrophage clearance of these cells. This enhanced resolution of inflammation was shown to be caspase-dependent as the effects of AT7519 were reduced by treatment with a broad spectrum caspase inhibitor (z-vad-fmk).Our data show that AT7519 induces human eosinophil apoptosis and enhances the resolution of a murine model of allergic pleurisy by inducing caspase-dependent eosinophil apoptosis and enhancing macrophage ingestion of apoptotic eosinophils. These findings demonstrate the utility of cyclin-dependent kinase inhibitors such as AT7519 as potential therapeutic agents for the treatment of eosinophil dominant allergic disorders

Alzheimer’s disease and cytokine IL-10 gene polymorphisms: is there an association?

ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia. In the last 15 years, a new theory has proposed the autoimmune mechanism as a trigger for AD. Studies on the association between AD and inflammatory biomarkers have yielded controversial results. Interleukin-10 (IL-10), an anti-inflammatory mediator, has been pointed out as one of the main cytokines associated with the occurrence of AD. Moreover, treatment that increases IL-10 levels could be a potential therapy for AD, since this cytokine acts on amyloid and pro-inflammatory molecule reduction. Based on the current literature, this study reviews evidence regarding the role of IL-10 polymorphisms in the context of AD, which has been shown to be of paramount importance for attenuating neuroinflammation, cognitive dysfunction and neurodegeneration

The dengue virus nonstructural protein 1 (NS1) increases NF-kB transcriptional activity in HepG2 cells.

Dengue virus nonstructural protein 1 (NS1) is a glycoprotein involved in viral RNA replication. NS1 associates with host cell proteins and can be found in lipid raft domains on the host cell surface, suggesting an involvement in signal transduction events. In this work, we observed that NS1 expression in HepG2 cells increases nuclear translocation of NF-jB p65 protein, which was paralleled by DNA-protein complex formation. Luciferase assays showed an increase in NF-jB transcriptional activities in NS1-expressing cells when compared to parental cells. NS1 may enhance NF-jB function in host cells and contribute to the pathogenesis of dengue

Annexin-A1-Derived Peptide Ac2-26 Suppresses Allergic Airway Inflammation and Remodelling in Mice

Annexin-A1 (AnxA1) and its N-terminal derived peptide Ac2-26 regulate the inflammatory response in several experimental models of disorders. This study evaluated the effect of endogenous AnxA1 and its N-terminal peptide Acetyl 2-26 (Ac2-26) on allergic asthma triggered by house dust mite (HDM) extract in mice. ANXA1−/− and wildtype (WT) mice were exposed to intranasal instillation of HDM every other day for 3 weeks, with analyses performed 24 h following the last exposure. Intranasal administration of peptide Ac2-26 was performed 1 h before HDM, beginning 1 week after the initial antigen application. ANXA1−/− mice stimulated with HDM showed marked exacerbations of airway hyperreactivity (AHR), eosinophil accumulation, subepithelial fibrosis, and mucus hypersecretion, all parameters correlating with overexpression of cytokines (IL-4, IL-13, TNF-α, and TGF-β) and chemokines (CCL11/eotaxin-1 and CCL2/MCP-1). Intranasal treatment with peptide Ac2-26 decreased eosinophil infiltration, peribronchiolar fibrosis, and mucus exacerbation caused by the allergen challenge. Ac2-26 also inhibited AHR and mediator production. Collectively, our findings show that the AnxA1-derived peptide Ac2-26 protects against several pathological changes associated with HDM allergic reaction, suggesting that this peptide or related AnxA1-mimetic Ac2-26 may represent promising therapeutic candidates for the treatment of allergic asthma

Inhibition of tissue inflammation and bacterial translocation as one of the protective mechanisms of Saccharomyces boulardii against Salmonella infection in mice.

Submitted by Nuzia Santos ([email protected]) on 2018-12-21T18:22:41Z No. of bitstreams: 1 Inhibition of tissue inflammation and bacterial translocation.pdf: 5745525 bytes, checksum: 20ce864a4910ae14276121be266f2f73 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-12-21T18:27:26Z (GMT) No. of bitstreams: 1 Inhibition of tissue inflammation and bacterial translocation.pdf: 5745525 bytes, checksum: 20ce864a4910ae14276121be266f2f73 (MD5)Made available in DSpace on 2018-12-21T18:27:26Z (GMT). No. of bitstreams: 1 Inhibition of tissue inflammation and bacterial translocation.pdf: 5745525 bytes, checksum: 20ce864a4910ae14276121be266f2f73 (MD5) Previous issue date: 2013Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Patologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrazilFaculdade de Fármacia. Departamento de Análises Clínicas e Toxicológicas. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisa René Rachou. Laboratório de Entomologia Médica. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisa René Rachou. Laboratório de Entomologia Médica. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, BrazilGrowing evidences suggest that Saccharomyces boulardii (SB) is efficacious against bacterial infections and inflammatory bowel diseases. This study investigated the effects of treatment with SB provided in a murine model of typhoid fever. Mice were divided into two groups: (1) control animals challenged with Salmonella Typhimurium (ST), and (2) animals receiving SB, and then challenged with ST. At days 0, 1, 5, 10 and 15 post-challenge, animals were euthanized and tissues collected to analyze bacterial translocation, cytokines, signaling pathways and histological analysis. Survival rate and animal weight were also evaluated. Treatment with SB increased survival rate and inhibited translocation of bacteria after ST challenge. Histological data showed that SB also protected mice against liver damage induced by ST. SB decreased levels of inflammatory cytokines and activation of mitogen-activated protein kinases (p38, JNK and ERK1/2), phospho-IκB, p65-RelA, phospho-jun and c-fos in the colon, signal pathways involved in the activation of inflammation induced by ST. Further experiments revealed that probiotic effects were due, at least in part, to the binding of ST to the yeast. Such binding diminishes ST translocation, resulting in decreased activation of signaling pathways which lead to intestinal inflammation in a murine model of typhoid fever

Angiotensin-(1-7) and Alamandine Promote Anti-inflammatory Response in Macrophages In Vitro and In Vivo

The renin-angiotensin system (RAS) peptides play an important role in inflammation. Resolution of inflammation contributes to restore tissue homeostasis, and it is characterized by neutrophil apoptosis and their subsequent removal by macrophages, which are remarkable plastic cells involved in the pathophysiology of diverse inflammatory diseases. However, the effects of RAS peptides on different macrophage phenotypes are still emerging. Here, we evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) and the most novel RAS peptide, alamandine, on resting (M0), proinflammatory M(LPS+IFN-γ), and anti-inflammatory M(IL-4) macrophage phenotypes in vitro, as well as on specific immune cell populations and macrophage subsets into the pleural cavity of LPS-induced pleurisy in mice. Our results showed that Ang-(1-7) and alamandine, through Mas and MrgD receptors, respectively, do not affect M0 macrophages but reduce the proinflammatory TNF-α, CCL2, and IL-1β transcript expression levels in LPS+IFN-γ-stimulated macrophages. Therapeutic administration of these peptides in LPS-induced inflammation in mice decreased the number of neutrophils and M1 (F4/80lowGr1+CD11bmed) macrophage frequency without affecting the other investigated macrophage subsets. Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. In conclusion, our work sheds light on the emerging proresolving properties of Ang-(1-7) and alamandine, opening new avenues for the treatment of inflammatory diseases

AT7519 drives granulocyte apoptosis as assessed by flow cytometry.

<p>Immunized mice were challenged with OVA and 24 h later received AT7519 or vehicle and apoptosis assessed by flow cytometry at 2, 4 and 6 h (A). (B) Typical flow cytometric profile of pleural lavage cells showing granulocytes and non-granulocyte cells gated on the basis of size and granularity. (C) Representative histograms of gated granulocytes from vehicle treated (i) and AT7519 treated (ii) animals as well as representative histograms of gated non-granulocyte cells from vehicle treated (iii) and AT7519 treated (iv) animals at 6 hours post treatment. ***P<0.001 when compared with vehicle-treated, OVA-injected mice.</p