scholarly journals Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus

2011 ◽  
Vol 80 (1) ◽  
pp. 410-417 ◽  
Author(s):  
Melissa A. Gessner ◽  
Jessica L. Werner ◽  
Lauren M. Lilly ◽  
Michael P. Nelson ◽  
Allison E. Metz ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Ex Vivo ◽  
Lung Cells ◽  
Lipocalin 2 ◽  
Beta Glucan ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Deficient Mice ◽  
Lung Defense

ABSTRACTWe have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility toAspergillus fumigatuslung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense againstA. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early afterA. fumigatuschallenge. Culturing cells from enzymatic lung digestsex vivofurther demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1β, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice.In vivoneutralization of IL-22 in the lungs of WT mice resulted in impairedA. fumigatuslung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden afterA. fumigatuschallenge in the presence of impaired IL-1α, tumor necrosis factor alpha (TNF-α), CCL3/MIP-1α, and CCL4/MIP-1β production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from bothA. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity againstA. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impairedA. fumigatusclearance. Moreover, lungS100a8,S100a9, andReg3gmRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense againstA. fumigatusis mediated by Dectin-1-dependent IL-22 production.

Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice

2000 ◽  
Vol 12 (12) ◽  
pp. 4447-4456 ◽  
Author(s):  
Rose-Marie Bluthe ◽  
Sophie Laye ◽  
Bruno Michaud ◽  
Chantal Combe ◽  
Robert Dantzer ◽  
...  
Keyword(s):  
Tumour Necrosis ◽  
Interleukin 1 ◽  
Tumour Necrosis Factor Alpha ◽  
Type I ◽  
Sickness Behaviour ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

scholarly journals Impaired platelet responses to thrombin and collagen in AKT-1–deficient mice

Blood ◽  
2004 ◽  
Vol 104 (6) ◽  
pp. 1703-1710 ◽  
Author(s):  
Juhua Chen ◽  
Sarmishtha De ◽  
Derek S. Damron ◽  
William S. Chen ◽  
Nissim Hay ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Dense Granules ◽  
Fibrinogen Binding ◽  
Downstream Effectors ◽  
Low Concentrations ◽  
Phosphoinositide 3 Kinase ◽  
Deficient Mice ◽  
Granule Release

Abstract We investigated the role of Akt-1, one of the major downstream effectors of phosphoinositide 3-kinase (PI3K), in platelet function using mice in which the gene for Akt-1 had been inactivated. Using ex vivo techniques, we showed that Akt-1-deficient mice exhibited impaired platelet aggregation and spreading in response to various agonists. These differences were most apparent in platelets activated with low concentrations of thrombin. Although Akt-1 is not the predominant Akt isoform in mouse platelets, its absence diminished the amount of total phospho-Akt and inhibited increases in intracellular Ca2+ concentration in response to thrombin. Moreover, thrombin-induced platelet α-granule release as well as release of adenosine triphosphate from dense granules was also defective in Akt-1-null platelets. Although the absence of Akt-1 did not influence expression of the major platelet receptors for thrombin and collagen, fibrinogen binding in response to these agonists was significantly reduced. As a consequence of impaired αIIbβ3 activation and platelet aggregation, Akt-1 null mice showed significantly longer bleeding times than wild-type mice. (Blood. 2004;104:1703-1710)

scholarly journals Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4+ T Cell Responses during Chronic Helicobacter pylori Infection

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Adria Carbo ◽  
Danyvid Olivares-Villagómez ◽  
Raquel Hontecillas ◽  
Josep Bassaganya-Riera ◽  
Rupesh Chaturvedi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Wild Type ◽  
Content Type ◽  
Interleukin 21 ◽  
H Pylori ◽  
Deficient Mice

ABSTRACTThe development of gastritis duringHelicobacter pyloriinfection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. pyloriinfection, we combined mathematical modeling of CD4+T cell differentiation within vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pyloristrain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. pyloricolonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. Thesein vivodata were used to calibrate anH. pyloriinfection-dependent, CD4+T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronicH. pyloriinfection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+splenocyte-specifictbx21androrcexpression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+T cell-specific IL-10 expression inH. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronicH. pyloriinfection in a STAT1- and STAT3-dependent manner, therefore playing a major role controllingH. pyloriinfection and gastritis.IMPORTANCEHelicobacter pyloriis the dominant member of the gastric microbiota in more than 50% of the world’s population.H. pyloricolonization has been implicated in gastritis and gastric cancer, as infection withH. pyloriis the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis duringH. pyloriinfection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized withH. pylorias an alternative to aggressive antibiotics.

scholarly journals Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models

2021 ◽  
Vol 22 (9) ◽  
pp. 4778
Author(s):  
Mark Joseph Maranan Desamero ◽  
Soo-Hyun Chung ◽  
Shigeru Kakuta
Keyword(s):  
Mouse Models ◽  
Deficient Mouse ◽  
Beta Glucan ◽  
Downstream Signaling ◽  
Beta Glucans ◽  
Fungal Immunity ◽  
Anti Fungal ◽  
Susceptibility And Resistance ◽  
Deficient Mice

Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.

scholarly journals Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against MurineLegionella pneumophilaPneumonia

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Yuta Nanjo ◽  
Michael W. Newstead ◽  
Tetsuji Aoyagi ◽  
Xianying Zeng ◽  
Kazuhisa Takahashi ◽  
...  
Keyword(s):  
Host Defense ◽  
Legionella Pneumophila ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Bacterial Clearance ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
M1 Polarization ◽  
Life Threatening ◽  
Deficient Mice

ABSTRACTLegionella pneumophilacauses life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense againstL. pneumophilainfection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused byL. pneumophila. Intratracheal (i.t.) administration ofL. pneumophilainduced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings forL. pneumophila-infected wild-type (WT) mice, the i.t. administration ofL. pneumophilato IL-36 receptor-deficient (IL-36R−/−) mice resulted in increased mortality, a delay in lung bacterial clearance, increasedL. pneumophiladissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R−/−mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines.Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R−/−mice compared to macrophages from WT mice. WhileL. pneumophila-induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α−/−mice resulted in mortality similar to that observed in IL-36R−/−mice, indicating redundant and overlapping roles for these cytokines in experimental murineL. pneumophilapneumonia.

scholarly journals Changes in the Molecular and Functional Phenotype of Bovine Monocytes during Theileria parva Infection

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Reginaldo G. Bastos ◽  
Kelly Sears ◽  
Kelcey D. Dinkel ◽  
Donald P. Knowles ◽  
Lindsay M. Fry
Keyword(s):  
Ex Vivo ◽  
Interleukin 1 ◽  
T Cell Response ◽  
Sub Saharan Africa ◽  
Cytotoxic T Cell ◽  
Theileria Parva ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Lethal Infection ◽  
Infected Cells

ABSTRACT Theileria parva is the causative agent of East Coast fever (ECF), a tick-borne disease that kills over a million cattle each year in sub-Saharan Africa. Immune protection against T. parva involves a CD8+ cytotoxic T cell response to parasite-infected cells. However, there is currently a paucity of knowledge regarding the role played by innate immune cells in ECF pathogenesis and T. parva control. Here, we demonstrate an increase in intermediate monocytes (CD14++ CD16+) with a concomitant decrease in the classical (CD14++ CD16−) and nonclassical (CD14+ CD16+) subsets at 12 days postinfection (dpi) during lethal infection but not during nonlethal T. parva infection. Ex vivo analyses of monocytes demonstrated upregulation of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) mRNA and increased nitric oxide production during T. parva lethal infection compared to nonlethal infection at 10 dpi. Interestingly, no significant differences in peripheral blood parasite loads were observed between lethally and nonlethally infected animals at 12 dpi. In vitro stimulation with T. parva schizont-infected cells or Escherichia coli lipopolysaccharide (LPS) resulted in significant upregulation of IL-1β production by monocytes from lethally infected cattle compared to those from nonlethally infected animals. Strikingly, monocytes from lethally infected animals produced significant amounts of IL-10 mRNA after stimulation with T. parva schizont-infected cells. In conclusion, we demonstrate that T. parva infection leads to alterations in the molecular and functional phenotypes of bovine monocytes. Importantly, since these changes primarily occur in lethal infection, they can serve as biomarkers for ECF progression and severity, thereby aiding in the standardization of protection assessment for T. parva candidate vaccines.

scholarly journals Enhancement of Methacholine-Evoked Tracheal Contraction Induced by Bacterial Lipopolysaccharides Depends on Epithelium and Tumor Necrosis Factor

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
T. Secher ◽  
F. Rodrigues Coelho ◽  
N. Noulin ◽  
A. Lino dos Santos Franco ◽  
V. Quesniaux ◽  
...  
Keyword(s):  
Contractile Response ◽  
Ex Vivo ◽  
Adaptor Protein ◽  
Respiratory Pattern ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Bacterial Lipopolysaccharides ◽  
Necrosis Factor

Inhaled bacterial lipopolysaccharides (LPSs) induce an acute tumour necrosis factor-alpha (TNF-α-) dependent inflammatory response in the murine airways mediated by Toll-like receptor 4 (TLR4) via the myeloid differentiation MyD88 adaptor protein pathway. However, the contractile response of the bronchial smooth muscle and the role of endogenous TNFα in this process have been elusive. We determined the in vivo respiratory pattern of C57BL/6 mice after intranasal LPS administration with or without the presence of increasing doses of methacholine (MCh). We found that LPS administration altered the basal and MCh-evoked respiratory pattern that peaked at 90 min and decreased thereafter in the next 48 h, reaching basal levels 7 days later. We investigated in controlled ex vivo condition the isometric contraction of isolated tracheal rings in response to MCh cholinergic stimulation. We observed that preincubation of the tracheal rings with LPS for 90 min enhanced the subsequent MCh-induced contractile response (hyperreactivity), which was prevented by prior neutralization of TNFα with a specific antibody. Furthermore, hyperreactivity induced by LPS depended on an intact epithelium, whereas hyperreactivity induced by TNFα was well maintained in the absence of epithelium. Finally, the enhanced contractile response to MCh induced by LPS when compared with control mice was not observed in tracheal rings from TLR4- or TNF- or TNF-receptor-deficient mice. We conclude that bacterial endotoxin-mediated hyperreactivity of isolated tracheal rings to MCh depends upon TLR4 integrity that signals the activation of epithelium, which release endogenous TNFα.

scholarly journals Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus

2013 ◽  
Vol 82 (3) ◽  
pp. 1315-1325 ◽  
Author(s):  
Lauren M. Lilly ◽  
Michaella Scopel ◽  
Michael P. Nelson ◽  
Ashley R. Burg ◽  
Chad W. Dunaway ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Allergic Bronchopulmonary Aspergillosis ◽  
Cell Contact ◽  
Mrna Levels ◽  
Colony Stimulating Factor ◽  
Content Type ◽  
Eosinophil Peroxidase ◽  
Stimulating Factor ◽  
Deficient Mice

ABSTRACTExposure to the moldAspergillus fumigatusmay result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated withA. fumigatusexposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance ofA. fumigatusfrom the lung. AcuteA. fumigatuschallenge in normal mice induced the recruitment of CD11b+Siglec F+Ly-6GloLy-6CnegCCR3+eosinophils to the lungs, which was accompanied by an increase in lungEpx(eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impairedA. fumigatusclearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression ofEpx(eosinophil peroxidase) andPrg2(major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity againstA. fumigtausin vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response afterA. fumigatusexposure.

scholarly journals Induction of Interleukin-4 (IL-4) by Legionella pneumophila Infection in BALB/c Mice and Regulation of Tumor Necrosis Factor Alpha, IL-6, and IL-1β

2000 ◽  
Vol 68 (9) ◽  
pp. 5234-5240 ◽  
Author(s):  
Catherine Newton ◽  
Shannon McHugh ◽  
Ray Widen ◽  
Noriya Nakachi ◽  
Thomas Klein ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Legionella Pneumophila ◽  
Tumor Necrosis ◽  
Ex Vivo ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT Infection of BALB/c mice with a sublethal concentration ofLegionella pneumophila causes an acute disease that is resolved by innate immune responses. The infection also initiates the development of adaptive Th1 responses that protect the mice from challenge infections. To study the early responses, cytokines induced during the first 24 h after infection were examined. In the serum, interleukin-12 (IL-12) was detectable by 3 h and peaked at 10 h, while gamma interferon was discernible by 5 h and peaked at 8 h. Similar patterns were observed in ex vivo cultures of splenocytes. A transient IL-4 response was also detected by 3 h postinfection in ex vivo cultures. BALB/c IL-4-deficient mice were more susceptible to L. pneumophila infection than were wild-type mice. The infection induced higher serum levels of acute-phase cytokines (tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6), and reducing TNF-α levels with antibodies protected the mice from death. Moreover, the addition of IL-4 to L. pneumophila-infected macrophage cultures suppressed the production of these cytokines. Thus, the lack of IL-4 in the deficient mice resulted in unchecked TNF-α production, which appeared to cause the mortality. Monocyte chemoattractant protein-1 (MCP-1), a chemokine that is induced by IL-4 during Listeria monocytogenesinfection, was detected at between 2 and 30 h after infection. However, MCP-1 did not appear to be induced by IL-4 or to be required for the TNF-α regulation by IL-4. The data suggest that the early increase in IL-4 serves to regulate the mobilization of acute phase cytokines and thus controls the potential harmful effects of these cytokines.

scholarly journals Enterococcus faecalisDemonstrates Pathogenicity through Increased Attachment in anEx VivoPolymicrobial Pulpal Infection

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Wayne Nishio Ayre ◽  
Genevieve Melling ◽  
Camille Cuveillier ◽  
Madhan Natarajan ◽  
Jessica L. Roberts ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Host Response ◽  
Ex Vivo ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Streptococcus Anginosus ◽  
Cell Counts ◽  
Tnf Α ◽  
Factor Alpha ◽  
Infection Types

ABSTRACTThis study investigated the host response to a polymicrobial pulpal infection consisting ofStreptococcus anginosusandEnterococcus faecalis, bacteria commonly implicated in dental abscesses and endodontic failure, using a validatedex vivorat tooth model. Tooth slices were inoculated with planktonic cultures ofS. anginosusorE. faecalisalone or in coculture atS. anginosus/E. faecalisratios of 50:50 and 90:10. Attachment was semiquantified by measuring the area covered by fluorescently labeled bacteria. Host response was established by viable histological cell counts, and inflammatory response was measured using reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry. A significant reduction in cell viability was observed for single and polymicrobial infections, with no significant differences between infection types (∼2,000 cells/mm2for infected pulps compared to ∼4,000 cells/mm2for uninfected pulps).E. faecalisdemonstrated significantly higher levels of attachment (6.5%) thanS. anginosusalone (2.3%) and mixed-species infections (3.4% for 50:50 and 2.3% for 90:10), with a remarkable affinity for the pulpal vasculature. Infections withE. faecalisdemonstrated the greatest increase in tumor necrosis factor alpha (TNF-α) (47.1-fold forE. faecalis, 14.6-fold forS. anginosus, 60.1-fold for 50:50, and 25.0-fold for 90:10) and interleukin 1β (IL-1β) expression (54.8-fold forE. faecalis, 8.8-fold forS. anginosus, 54.5-fold for 50:50, and 39.9-fold for 90:10) compared to uninfected samples. Immunohistochemistry confirmed this, with the majority of inflammation localized to the pulpal vasculature and odontoblast regions. Interestingly,E. faecalissupernatant and heat-killedE. faecalistreatments were unable to induce the same inflammatory response, suggestingE. faecalispathogenicity in pulpitis is linked to its greater ability to attach to the pulpal vasculature.

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