IL-4 activates equine neutrophils and induces a mixed inflammatory cytokine expression profile with enhanced neutrophil chemotactic mediator release ex vivo

2010 ◽  
Vol 299 (4) ◽  
pp. L472-L482 ◽  
Author(s):  
Anouk Lavoie-Lamoureux ◽  
Kantuta Moran ◽  
Guy Beauchamp ◽  
Susanne Mauel ◽  
Falko Steinbach ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Allergic Airway Inflammation ◽  
Type I ◽  
Cytokine Expression Profile ◽  
Th2 Cytokine ◽  
Blood Neutrophils ◽  
Chemotactic Factors ◽  
Antigenic Exposure

Neutrophils are potent contributors to the lung pathophysiological changes occurring in allergic airway inflammation, which typically involve T helper type 2 (Th2) cytokine overexpression. We have previously reported that equine pulmonary endothelial cells are activated by the Th2 cytokine IL-4 and express chemotactic factors for neutrophils after stimulation. We have further explored the possible mechanisms linking Th2-driven inflammation and neutrophilia by studying the effects of recombinant equine IL-4, a prototypical Th2 cytokine, on peripheral blood neutrophils (PBN) isolated from normal animals and from horses with asthmatic airway inflammation (equine heaves). We found that IL-4 induced morphological changes in PBN, dose- and time-dependent expression of IL-8 mRNA, as well as the release of chemotactic factors for neutrophils in culture supernatants. Also, IL-4 induced a mixed inflammatory response in PBN from control and asthmatic-animals with increased expression of proinflammatory IL-8 and TNF-α but a marked inhibition of IL-1β. IL-4 type I receptor (IL-4Rα) and CD23 (FcϵRII) expression were also upregulated by IL-4. Importantly, disease as well as chronic antigenic exposure modified gene expression by PBN. Finally, we found that activation of equine neutrophils with IL-4 involved STAT6 phosphorylation and p38 MAPK and phosphatidylinositol 3-kinase (PI3K); the pharmacological inhibitors, SB-203580 and LY-294002, respectively, significantly reversed IL-4-induced gene modulation in PBN. Overall, results from this study add to the link between Th2-driven inflammation and neutrophilia in the equine model and further extend the characterization of IL-4 effects on neutrophils.

scholarly journals Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

2014 ◽  
Vol 82 (9) ◽  
pp. 3723-3739 ◽  
Author(s):  
Daniel E. Dulek ◽  
Dawn C. Newcomb ◽  
Kasia Goleniewska ◽  
Jaqueline Cephus ◽  
Weisong Zhou ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Airway Inflammation ◽  
Ex Vivo ◽  
Allergic Airway Inflammation ◽  
Dependent Manner ◽  
Content Type ◽  
Th2 Cytokine ◽  
Interleukin 17A ◽  
Th17 Cytokines

ABSTRACTThe Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, includingKlebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminishex vivoandin vivoIL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection withK. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acuteK. pneumoniaeinfection and thereby increases the lungK. pneumoniaeburden. As hypothesized, we found that allergic airway inflammation decreased the number ofK. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lungK. pneumoniaeburden and postinfection mortality. We showed that the decreased lungK. pneumoniaeburden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lungK. pneumoniaeburden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity againstK. pneumoniaeand suggest new mechanisms of orchestrating lung antibacterial immunity.

scholarly journals 2215

2017 ◽  
Vol 1 (S1) ◽  
pp. 3-3
Author(s):  
Timothy P. Moran ◽  
Robert M. Immormino ◽  
Hideki Nakano ◽  
David Peden ◽  
Donald N. Cook
Keyword(s):  
Flow Cytometry ◽  
Airway Inflammation ◽  
Allergic Asthma ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Allergic Airway Inflammation ◽  
Surface Protein ◽  
Fold Increase ◽  
Deficient Mice

OBJECTIVES/SPECIFIC AIMS: Allergic asthma is a chronic lung disease driven by inappropriate inflammatory responses against inhaled allergens. Neuropilin-2 (NRP2) is a pleiotropic transmembrane receptor expressed in the lung, but its role in allergic airway inflammation is unknown. Here, we characterized NRP2 expression in lung immune cells and investigated the effects of NRP2 deficiency on airway inflammation. METHODS/STUDY POPULATION: NRP2 expression by lung immune cells from NRP2 reporter mice was determined by flow cytometry. NRP2 expression by human alveolar macrophages (AM) from healthy individuals was determined by mRNA analysis and flow cytometry. Airway inflammation in NRP2-deficient mice was assessed by bronchoalveolar lavage (BAL) cytology and inflammatory gene expression in lung tissue. RESULTS/ANTICIPATED RESULTS: NRP2 expression in lung immune cells was negligible under steady-state conditions. In contrast, inhalational exposure to lipopolysaccharide (LPS) adjuvant dramatically induced NRP2 expression in AM, as 63.3% of AM from LPS-treated mice were NRP2+ compared with 1.5% of AM from control mice. Ex vivo treatment of human AM with LPS resulted in a 1.5-fold and 2.6-fold increase in NRP2 mRNA and surface protein expression, respectively. Compared to littermate controls, NRP2-deficient mice had greater numbers of BAL leukocytes and increased lung expression of the T helper type 2 cytokines IL-4 and IL-5. Furthermore, NRP2 deficiency resulted in stochastic development of allergic airway inflammation, as spontaneous airway eosinophilia was detected in 25% (2/8) of NRP2-deficient mice compared with 0% (0/8) of littermate controls. DISCUSSION/SIGNIFICANCE OF IMPACT: NRP2 is expressed by activated human and murine AM and suppresses the spontaneous development of allergic airway inflammation. These findings suggest that NRP2 may play a key role in allergic asthma pathogenesis, and could prove to be an important therapeutic target in patients with asthma and other allergic diseases.

scholarly journals Exacerbation of Allergic Airway Inflammation in Mice Lacking ECTO-5′-Nucleotidase (CD73)

2020 ◽  
Vol 11 ◽  
Author(s):  
Elisabetta Caiazzo ◽  
Ida Cerqua ◽  
Maria Antonietta Riemma ◽  
Roberta Turiello ◽  
Armando Ialenti ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Sensitization ◽  
Adaptive Immune Response ◽  
Allergic Airway Inflammation ◽  
Individual Response ◽  
Type I ◽  
Target Tissue ◽  
Extracellular Adenosine ◽  
Reduced Frequency

The airways are a target tissue of type I allergies and atopy is the main etiological factor of bronchial asthma. A predisposition to allergy and individual response to allergens are dependent upon environmental and host factors. Early studies performed to clarify the role of extracellular adenosine in the airways highlighted the importance of adenosine-generating enzymes CD73, together with CD39, as an innate protection system against lung injury. In experimental animals, deletion of CD73 has been associated with immune and autoimmune diseases. Our experiments have been performed to investigate the role of CD73 in the assessment of allergic airway inflammation following sensitization. We found that in CD73−/− mice sensitization, induced by subcutaneous ovalbumin (OVA) administration, increased signs of airway inflammation and atopy developed, characterized by high IgE plasma levels and increased pulmonary cytokines, reduced frequency of lung CD4+CD25+Foxp3+ T cells, but without bronchial hyperreactivity, compared to sensitized wild type mice. Our results provide evidence that the lack of CD73 causes an uncontrolled allergic sensitization, suggesting that CD73 is a key molecule at the interface between innate and adaptive immune response. The knowledge of host immune factors controlling allergic sensitization is of crucial importance and might help to find preventive interventions that could act before an allergy develops.

scholarly journals Plasma Proteins and Platelets Modulate Neutrophil Clearance of Malaria-Related Hemozoin Crystals

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 93 ◽  
Author(s):  
Sueli de Oliveira Silva Lautenschlager ◽  
Tehyung Kim ◽  
Danielle Lazarim Bidóia ◽  
Celso Vataru Nakamura ◽  
Hans-Joachim Anders ◽  
...  
Keyword(s):  
Human Plasma ◽  
Plasma Proteins ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Neutrophil Extracellular Traps ◽  
Selective Exposure ◽  
Dependent Manner ◽  
Membrane Rupture ◽  
Extracellular Traps ◽  
Blood Neutrophils

Hemozoin is an insoluble crystalline pigment produced by the malaria parasite Plasmodia upon digesting host hemoglobin inside red blood cells. Red blood cell rupture releases hemozoin crystals into the circulation from where they are cleared by phagocytes such as neutrophils. We speculated that plasma proteins would affect the ability of neutrophils to clear hemozoin crystals. To test this, we cultured human blood neutrophils with hemozoin ex vivo and found that neutrophils ingested hemozoin (0.1–1 µm crystal size) in a dose-dependent manner into phagosomes and vesicles/vacuoles, resulting in morphological changes including nuclear enlargement, and vesicle formation, but not cell membrane rupture or release of neutrophil extracellular traps. The presence of human plasma significantly inhibited the ability of neutrophils to ingest hemozoin crystals. Platelet-poor plasma further inhibited the uptake of hemozoin by neutrophils. Selective exposure to fibrinogen completely replicated the plasma effect. Taken together, neutrophils cleared hemozoin crystals from the extracellular space via endocytosis into phagosomes and vesicles without inducing the release of neutrophil extracellular traps. However, human plasma components such as fibrinogen limited hemozoin clearance, whereas the presence of platelets augmented this process. These factors may influence the pro-inflammatory potential of hemozoin crystals in malaria.

Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma

2011 ◽  
Vol 301 (6) ◽  
pp. L975-L984 ◽  
Author(s):  
Guqin Zhang ◽  
Hanxiang Nie ◽  
Jiong Yang ◽  
Xuhong Ding ◽  
Yi Huang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Airway Inflammation ◽  
Cell Activation ◽  
Cell Function ◽  
Allergic Airway Inflammation ◽  
Nkt Cells ◽  
Chronic Inflammatory Disease ◽  
Type I ◽  
Type Ii ◽  
Nkt Cell

Asthma is a common chronic inflammatory disease involving many different cell types. Recently, type I natural killer T (NKT) cells have been demonstrated to play a crucial role in the development of asthma. However, the roles of type II NKT cells in asthma have not been investigated before. Interestingly, type I and type II NKT cells have been shown to have opposing roles in antitumor immunity, antiparasite immunity, and autoimmunity. We hypothesized that sulfatide-activated type II NKT cells could prevent allergic airway inflammation by inhibiting type I NKT cell function in asthma. Strikingly, in our mouse model, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells result in reduced-inflammation cell infiltration in the lung and bronchoalveolar lavage fluid, decreased levels of IL-4 and IL-5 in the BALF; and decreased serum levels of ovalbumin-specific IgE and IgG1. Furthermore, it is found that the activation of sulfatide-reactive type II NKT cells leads to the functional inactivation of type I NKT cells, including the proliferation and cytokine secretion. Our data reveal that type II NKT cells activated by glycolipids, such as sulfatide, may serve as a novel approach to treat allergic diseases and other disorders characterized by inappropriate type I NKT cell activation.

scholarly journals Cellular FLIP Long Form-Transgenic Mice Manifest a Th2 Cytokine Bias and Enhanced Allergic Airway Inflammation

2004 ◽  
Vol 172 (8) ◽  
pp. 4724-4732 ◽  
Author(s):  
Wenfang Wu ◽  
Lisa Rinaldi ◽  
Karen A. Fortner ◽  
Jennifer Q. Russell ◽  
Jürg Tschopp ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Th2 Cytokine ◽  
Long Form ◽  
Cellular Flip

scholarly journals Sulfatide-activated type II NKT cells suppress immunogenic maturation of lung dendritic cells in murine models of asthma

2019 ◽  
Vol 317 (5) ◽  
pp. L578-L590
Author(s):  
Huaqin Pan ◽  
Guqin Zhang ◽  
Hanxiang Nie ◽  
Shuhua Li ◽  
Shaojun He ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Airway Inflammation ◽  
Mouse Models ◽  
Adoptive Transfer ◽  
Allergic Airway Inflammation ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Functional Maturation

Our previous study showed that sulfatide-activated type II natural killer T (NKT) cells can prevent allergic airway inflammation in an ovalbumin (OVA)-induced murine model of asthma, but the underlying mechanism is unclear. Recently, sulfatide-activated type II NKT cells were shown to modulate the function of dendritic cells in experimental autoimmune encephalomyelitis and nonobese diabetic mice. Thus, it was hypothesized that sulfatide-activated type II NKT cells may modulate the function of lung dendritic cells (LDCs) in asthmatic mice. Our data showed that, in our mouse models, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells resulted in reduced expression of surface maturation markers and proinflammatory cytokine production of LDCs. LDCs from sulfatide-treated asthmatic mice, in contrast to LDCs from PBS-treated asthmatic mice, significantly reduced allergic airway inflammation in vivo. However, we found no influence of sulfatide-activated type II NKT cells on the phenotypic and functional maturation of bone marrow-derived dendritic cells in vitro. In addition, adoptive transfer of sulfatide-activated type II NKT cells did not influence the phenotypic and functional maturation of LDCs in CD1d−/− mice, which lack both type I and II NKT cells, immunized and challenged with OVA. Our data reveal that sulfatide-activated type II NKT cells can suppress immunogenic maturation of LDCs to reduce allergic airway inflammation in mouse models of asthma, and it is possible that the immunomodulatory effect needs type I NKT cells.

scholarly journals Resolved Influenza A Virus Infection Has Extended Effects on Lung Homeostasis and Attenuates Allergic Airway Inflammation in a Mouse Model

2020 ◽  
Vol 8 (12) ◽  
pp. 1878
Author(s):  
Qingyu Wu ◽  
Ilka Jorde ◽  
Olivia Kershaw ◽  
Andreas Jeron ◽  
Dunja Bruder ◽  
...  
Keyword(s):  
Mouse Model ◽  
Airway Inflammation ◽  
Influenza A Virus ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Acute Infection ◽  
Allergic Airway Inflammation ◽  
Airway Hyperreactivity ◽  
Sublethal Dose

Allergic airway inflammation (AAI) involves T helper cell type 2 (Th2) and pro-inflammatory responses to aeroallergens and many predisposing factors remain elusive. Influenza A virus (IAV) is a major human pathogen that causes acute respiratory infections and induces specific immune responses essential for viral clearance and resolution of the infection. Beyond acute infection, IAV has been shown to persistently affect lung homeostasis and respiratory immunity. Here we asked how resolved IAV infection affects subsequently induced AAI. Mice infected with a sublethal dose of IAV were sensitized and challenged in an ovalbumin mediated mouse model for AAI after resolution of the acute viral infection. Histological changes, respiratory leukocytes, cytokines and airway hyperreactivity were analyzed in resolved IAV infection alone and in AAI with and without previous IAV infection. More than five weeks after infection, we detected persistent pneumonia with increased activated CD4+ and CD8+ lymphocytes as well as dendritic cells and MHCII expressing macrophages in the lung. Resolved IAV infection significantly affected subsequently induced AAI on different levels including morphological changes, respiratory leukocytes and lymphocytes as well as the pro-inflammatory cytokine responses, which was clearly diminished. We conclude that IAV has exceptional persisting effects on respiratory immunity with substantial consequences for subsequently induced AAI.

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