scholarly journals Requirement for the Chemokine Receptor Ccr6 in Allergic Pulmonary Inflammation

2001 ◽  
Vol 194 (4) ◽  
pp. 551-556 ◽  
Author(s):  
Nicholas W. Lukacs ◽  
Dina M. Prosser ◽  
Maria Wiekowski ◽  
Sergio A. Lira ◽  
Donald N. Cook
Keyword(s):  
Cytokine Production ◽  
Immunoglobulin E ◽  
Pulmonary Inflammation ◽  
Allergen Challenge ◽  
Serum Levels ◽  
Airway Hyperreactivity ◽  
Wild Type ◽  
Interleukin 5 ◽  
Helper Cell Type ◽  
Deficient Mice

Allergic asthmatic responses in the airway are associated with airway hyperreactivity, eosinophil accumulation in the lung, and cytokine production by allergen-specific, T helper cell type 2 (Th2) lymphocytes. Here, we show that in a cockroach antigen (CA) model of allergic pulmonary inflammation, the chemokine macrophage inflammatory protein (MIP)-3α is expressed in the lung within hours of allergen challenge. To determine the biologic relevance of this expression, mice lacking CCR6, the only known receptor for MIP-3α, were studied for their response to CA. CCR6-deficient mice were immunized to the same extent as their wild-type counterparts, as judged by cytokine production in antigen-challenged lymphocytes. However, compared with CA-challenged wild-type mice, challenged CCR6-deficient mice had reduced airway resistance, fewer eosinophils around the airway, lower levels of interleukin 5 in the lung, and reduced serum levels of immunoglobulin E. Together, these data demonstrate that MIP-3α and CCR6 function in allergic pulmonary responses and suggest that these molecules might represent novel therapeutic targets for treatment of asthma.

scholarly journals Onset of obesity in carboxypeptidase E-deficient mice and effect on airway responsiveness and pulmonary responses to ozone

2010 ◽  
Vol 108 (6) ◽  
pp. 1812-1819 ◽  
Author(s):  
Richard A. Johnston ◽  
Ming Zhu ◽  
Christopher B. Hernandez ◽  
Erin S. Williams ◽  
Stephanie A. Shore
Keyword(s):  
Bronchoalveolar Lavage Fluid ◽  
Forced Oscillation ◽  
Pulmonary Inflammation ◽  
Age Groups ◽  
Serum Levels ◽  
Lavage Fluid ◽  
Airway Responsiveness ◽  
Wild Type ◽  
Satiety Hormone ◽  
Deficient Mice

When compared with lean, wild-type mice, obese Cpe fat mice, 14 wk of age and older, manifest innate airway hyperresponsiveness (AHR) to intravenous methacholine and enhanced pulmonary inflammation following acute exposure to ozone (O3). The purpose of this study was to examine the onset of these augmented pulmonary responses during the onset of obesity. Thus airway responsiveness and O3-induced pulmonary inflammation and injury were examined in 7- and 10-wk-old Cpe fat and age-matched, wild-type, C57BL/6 mice. Compared with age-matched controls, 7- and 10-wk-old Cpe fat mice were approximately 25 and 61% heavier, respectively. Airway responsiveness to intravenous methacholine was assessed via forced oscillation in unexposed Cpe fat and wild-type mice. The 10- but not 7-wk-old Cpe fat mice exhibited innate AHR. O3 exposure (2 ppm for 3 h) increased markers of pulmonary inflammation and injury in the bronchoalveolar lavage fluid of all mice. However, most markers were greater in Cpe fat vs. wild-type mice, regardless of age. Serum levels of leptin, a satiety hormone and proinflammatory cytokine, were increased in Cpe fat vs. wild-type mice of both age groups, but the serum levels of other systemic inflammatory markers were greater only in 10-wk-old Cpe fat vs. wild-type mice. These results demonstrate that a 25% increase in body weight is sufficient to augment pulmonary responses to O3, but innate AHR is not manifest until the mice become much heavier. These results suggest that the mechanistic bases for these responses are different and may develop according to the nature and degree of the chronic systemic inflammation that is present.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

2019 ◽  
Vol 20 (20) ◽  
pp. 4989 ◽  
Author(s):  
Yoshinori Tanino ◽  
Xintao Wang ◽  
Takefumi Nikaido ◽  
Kenichi Misa ◽  
Yuki Sato ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Heparan Sulfate ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Lung Fibroblasts ◽  
Fibrosis Score ◽  
Wild Type ◽  
Deficient Mice

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

scholarly journals Characterization of Chronic Cutaneous Lesions from TNF-Receptor-1-Deficient Mice Infected byLeishmania major

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Carolina Ferreira Oliveira ◽  
Daniel Manzoni-de-Almeida ◽  
Paula Seixas Mello ◽  
Caio Cotta Natale ◽  
Helton da Costa Santiago ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Cytokine Production ◽  
Late Time ◽  
Tnf Receptor ◽  
Wild Type ◽  
Clinical Form ◽  
Cutaneous Lesions ◽  
Migration Of Cells ◽  
Deficient Mice

Leishmania major-infected TNF receptor 1 deficient (TNFR1 KO) mice resolve parasitism but fail to resolve lesions, while wild-type mice completely heal. We investigated the cell composition, cytokine production, and apoptosis in lesions fromL. major-infected TNFR1 KO and wild-type (WT) mice. Chronic lesions fromL. major-infected TNFR1 KO mice presented larger number of CD8+ T and Ly6G+ cells. In addition, higher concentrations of mRNA for IFN-γCCL2 and CCL5, as well as protein, but lower numbers of apoptotic cells, were found in lesions from TNFR1 KO mice than in WT, at late time points of infection. Our studies showed that persistent lesions inL. major-infected TNFR1 KO mice may be mediated by continuous migration of cells to the site of inflammation due to the presence of chemokines and also by lower levels of apoptosis. We suggest that this model has some striking similarities to the mucocutaneous clinical form of leishmaniasis.

scholarly journals Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti–Tim-3 antibody in vivo

2007 ◽  
Vol 204 (6) ◽  
pp. 1289-1294 ◽  
Author(s):  
Jennifer Kearley ◽  
Sarah J. McMillan ◽  
Clare M. Lloyd
Keyword(s):  
Pulmonary Inflammation ◽  
Allergen Challenge ◽  
Airway Hyperreactivity ◽  
Th2 Cells ◽  
Antibody Treatment ◽  
Th2 Response ◽  
Th2 Cytokine ◽  
Cytokine Levels ◽  
Ifn Γ

T cell immunoglobulin and mucin domain–containing molecule-3 (Tim-3) is a surface molecule that is preferentially expressed on activated Th1 cells in comparison to Th2 cells. Blockade of Tim-3 has been shown to enhance Th1-driven pathology in vivo, suggesting that blockade of Tim-3 may improve the development of Th2-associated responses such as allergy. To examine the effects of Tim-3 blockade on the Th2 response in vivo, we administered anti–Tim-3 antibody during pulmonary inflammation induced by transfer of ovalbumin (OVA)-reactive Th2 cells, and subsequent aerosol challenge with OVA. In this model, anti–Tim-3 antibody treatment before each airway challenge significantly reduced airway hyperreactivity, with a concomitant decrease in eosinophils and Th2 cells in the lung. We examined Th1 and Th2 cytokine levels in the lung after allergen challenge and found that pulmonary expression of the Th2 cytokine IL-5 was significantly reduced, whereas IFN-γ levels were significantly increased by anti–Tim-3 antibody treatment. Thus, blocking Tim-3 function has a beneficial effect during pulmonary inflammation by skewing the Th2 response toward that of a Th1 type, suggesting an important role for Tim-3 in the regulation of allergic disease.

scholarly journals Differential Role of MyD88 in Macrophage-Mediated Responses to Opportunistic Fungal Pathogens

2003 ◽  
Vol 71 (9) ◽  
pp. 5280-5286 ◽  
Author(s):  
Kieren A. Marr ◽  
S. Arunmozhi Balajee ◽  
Thomas R. Hawn ◽  
Adrian Ozinsky ◽  
Uyenvy Pham ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Cytokine Production ◽  
Pathogenic Fungi ◽  
Adapter Protein ◽  
Wild Type ◽  
Intracellular Killing ◽  
Pathogenic Yeast ◽  
Myd88 Signaling ◽  
Deficient Mice

ABSTRACT Toll-like receptors mediate macrophage recognition of microbial ligands, inducing expression of microbicidal molecules and cytokines via the adapter protein MyD88. We investigated the role of MyD88 in regulating murine macrophage responses to a pathogenic yeast (Candida albicans) and mold (Aspergillus fumigatus). Macrophages derived from bone marrow of MyD88-deficient mice (MyD88−/−) demonstrated impaired phagocytosis and intracellular killing of C. albicans compared to wild-type (MyD88+/+) macrophages. In contrast, ingestion and killing of A. fumigatus conidia was MyD88 independent. Cytokine production by MyD88−/− macrophages in response to C. albicans yeasts and hyphae was substantially decreased, but responses to A. fumigatus hyphae were preserved. These results provide evidence that MyD88 signaling is involved in phagocytosis and killing of live C. albicans, but not A. fumigatus. The differential role of MyD88 may represent one mechanism by which macrophages regulate innate responses specific to different pathogenic fungi.

scholarly journals Respiratory Tract Infection with Mycoplasma pneumoniae in Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation

2006 ◽  
Vol 75 (1) ◽  
pp. 236-242 ◽  
Author(s):  
C. M. Salvatore ◽  
M. Fonseca-Aten ◽  
K. Katz-Gaynor ◽  
A. M. Gomez ◽  
A. Mejias ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Mycoplasma Pneumoniae ◽  
Pulmonary Inflammation ◽  
Airway Hyperreactivity ◽  
Interleukin 12 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniae respiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 107 CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniae were found to have significantly lower BAL M. pneumoniae concentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN-γ than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P = 0.065) and TNF-α (P = 0.078). No differences were found for IL-1β, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniae pneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.

scholarly journals Effect of antigen sensitization and challenge on oscillatory mechanics of the lung and pulmonary inflammation in obese carboxypeptidase E-deficient mice

2014 ◽  
Vol 307 (6) ◽  
pp. R621-R633 ◽  
Author(s):  
Paul H. Dahm ◽  
Jeremy B. Richards ◽  
Harry Karmouty-Quintana ◽  
Kevin R. Cromar ◽  
Sanjiv Sur ◽  
...  
Keyword(s):  
Airway Obstruction ◽  
Genetic Basis ◽  
Bronchoalveolar Lavage Fluid ◽  
Leptin Receptor ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Wild Type ◽  
Carboxypeptidase E ◽  
Genetic Deficiency ◽  
Deficient Mice

Atopic, obese asthmatics exhibit airway obstruction with variable degrees of eosinophilic airway inflammation. We previously reported that mice obese as a result of a genetic deficiency in either leptin ( ob/ ob mice) or the long isoform of the leptin receptor ( db/ db mice) exhibit enhanced airway obstruction in the presence of decreased numbers of bronchoalveolar lavage fluid (BALF) eosinophils compared with lean, wild-type mice following antigen (ovalbumin; OVA) sensitization and challenge. To determine whether the genetic modality of obesity induction influences the development of OVA-induced airway obstruction and OVA-induced pulmonary inflammation, we examined indices of these sequelae in mice obese as a result of a genetic deficiency in carboxypeptidase E, an enzyme that processes prohormones and proneuropeptides involved in satiety and energy expenditure ( Cpe fat mice). Accordingly, Cpe fat and lean, wild-type (C57BL/6) mice were sensitized to OVA and then challenged with either aerosolized PBS or OVA. Compared with genotype-matched, OVA-sensitized and PBS-challenged mice, OVA sensitization and challenge elicited airway obstruction and increased BALF eosinophils, macrophages, neutrophils, IL-4, IL-13, IL-18, and chemerin. However, OVA challenge enhanced airway obstruction and pulmonary inflammation in Cpe fat compared with wild-type mice. These results demonstrate that OVA sensitization and challenge enhance airway obstruction in obese mice regardless of the genetic basis of obesity, whereas the degree of OVA-induced pulmonary inflammation is dependent on the genetic modality of obesity induction. These results have important implications for animal models of asthma, as modeling the pulmonary phenotypes for subpopulations of atopic, obese asthmatics critically depends on selecting the appropriate mouse model.

scholarly journals Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

2003 ◽  
Vol 197 (6) ◽  
pp. 703-709 ◽  
Author(s):  
Nancy Wood ◽  
Matthew J. Whitters ◽  
Bruce A. Jacobson ◽  
JoAnn Witek ◽  
Joseph P. Sypek ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immunoglobulin E ◽  
Interferon Γ ◽  
Wild Type ◽  
Functional Importance ◽  
Bone Marrow Macrophage ◽  
Tissue Macrophage ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Deficient Mice

Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)α and IL-13Rα1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Rα2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Rα2, mice deficient in IL-13Rα2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Rα2−/− mice despite the fact that serum IL-13 was absent and immune interferon γ production increased compared with wild-type mice. IL-13Rα2–deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Rα2 in regulating immune responses in wild-type mice.

scholarly journals C4b binding protein negatively regulates TLR1/2 response

2016 ◽  
Vol 23 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Naoko Morita ◽  
Ikuko Yamai ◽  
Koichiro Takahashi ◽  
Yutaka Kusumoto ◽  
Takuma Shibata ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Binding Protein ◽  
Negative Regulation ◽  
Negative Regulator ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
Inflammatory Signals ◽  
Deficient Mice

TLR2 associates with TLR1 and recognizes microbial lipoproteins. Pam3CSK4, a triacylated lipoprotein, is anchored to the extracellular domain of TLR1 and TLR2 and induces pro-inflammatory signals. Here we show that C4b binding protein (C4BP), which is a complement pathway inhibitor, is a TLR2-associated molecule. Immunoprecipitation assay using anti-TLR2 mAb shows that C4BP binds to TLR2. In C4BP-deficient mice, Pam3CSK4-induced IL-6 levels were increased compared with wild type mice. In C4BP-expressing cells, Pam3CSK4-induced IL-8 production was reduced depending on the C4BP expression levels. These results reveal the important role of C4BP in negative regulation of TLR1/2-dependent pro-inflammatory cytokine production. Furthermore, using a fluorescent conjugated Pam3CSK4, we show that C4BP blocks the binding of Pam3CSK4 to TLR1/2. Finally, we show that exogenous C4BP also inhibits Pam3CSK4-induced signaling leading to IL-8 production. Our results indicate C4BP binding to TLR2 and consequent neutralization of its activity otherwise inducing pro-inflammatory cytokine production. C4BP is a negative regulator of TLR1/2 activity.

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