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1.
J Allergy Clin Immunol ; 149(5): 1802-1806.e2, 2022 05.
Article in English | MEDLINE | ID: mdl-34740605

ABSTRACT

BACKGROUND: The roles of systemic and airway-specific epithelial energy metabolism in altering the developmental programming of airway epithelial cells (AECs) in early life are poorly understood. OBJECTIVE: Our aim was to assess carbohydrate metabolism in developing AECs among children with and without wheeze and test the association of infant plasma energy biomarkers with subsequent recurrent wheeze and asthma outcomes. METHODS: We measured cellular carbohydrate metabolism in live nasal AECs collected at age 2 years from 15 male subjects with and without a history of wheeze and performed a principal component analysis to visually assess clustering of data on AEC metabolism of glycolitic metabolites and simple sugars. Among 237 children with available year 1 plasma samples, we tested the associations of year 1 plasma energy biomarkers and recurrent wheeze and asthma by using generalized estimating equations and logistic regression. RESULTS: Children with a history of wheeze had lower utilization of glucose in their nasal AECs than did children with no wheeze. Systemically, a higher plasma glucose concentration at year 1 (within the normal range) was associated with decreased odds of asthma at age 5 years (adjusted odds ratio = 0.56; 95% CI = 0.35-0.90). Insulin concentration, glucose-to-insulin ratio, C-peptide concentration, and leptin concentration at year 1 were associated with recurrent wheeze from age 2 years to age 5 years. CONCLUSION: These results suggest that there is significant energy metabolism dysregulation in early life, which likely affects AEC development. These pertubations of epithelial cell metabolism in infancy may have lasting effects on lung development that could render the airway more susceptible to allergic sensitization.


Subject(s)
Asthma , Insulins , Biomarkers , Child, Preschool , Female , Glucose , Humans , Male , Respiratory Sounds
2.
J Immunol ; 204(2): 438-448, 2020 01 15.
Article in English | MEDLINE | ID: mdl-31818982

ABSTRACT

In inflamed human tissues, we often find intact eosinophilic granules, but not eosinophils themselves. Eosinophils, tissue-dwelling granulocytes with several homeostatic roles, have a surprising association with fibrinogen and tissue remodeling. Fibrinogen is a complex glycoprotein with regulatory roles in hemostasis, tumor development, wound healing, and atherogenesis. Despite its significance, the functional link between eosinophils and fibrinogen is not understood. We tested IL-5-primed mouse bone marrow-derived and human blood-sorted eosinophil activity against FITC-linked fibrinogen substrates. The interactions between these scaffolds and adhering eosinophils were quantified using three-dimensional laser spectral, confocal, and transmission electron microscopy. Eosinophils were labeled with major basic protein (MBP) Ab to visualize granules and assessed by flow cytometry. Both mouse and human eosinophils showed firm adhesion and degraded up to 27 ± 3.1% of the substrate area. This co-occurred with active MBP-positive granule release and the expression of integrin CD11b. Mass spectrometry analysis of fibrinogen proteolytic reactions detected the presence of eosinophil peroxidase, MBP, and fibrin α-, ß-, and γ-chains. Eosinophil activity was adhesion dependent, as a blocking Ab against CD11b significantly reduced adhesion, degranulation, and fibrinogenolysis. Although adhered, eosinophils exhibited no proteolytic activity on collagen matrices. Cytolytic degranulation was defined by loss of membrane integrity, cell death, and presence of cell-free granules. From transmission electron microscopy images, we observed only fibrinogen-exposed eosinophils undergoing this process. To our knowledge, this is the first report to show that fibrinogen is a specific trigger for cytolytic eosinophil degranulation with implications in human disease.


Subject(s)
Eosinophils/immunology , Fibrinogen/metabolism , Inflammation/metabolism , Animals , CD11b Antigen/metabolism , Cell Adhesion , Cell Death , Cell Degranulation , Cells, Cultured , Cytotoxicity, Immunologic , Eosinophil Major Basic Protein/metabolism , Humans , Inflammation/immunology , Interleukin-5/metabolism , Mice , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Secretory Vesicles/metabolism
3.
Int Arch Allergy Immunol ; 182(8): 663-678, 2021.
Article in English | MEDLINE | ID: mdl-34077948

ABSTRACT

Concomitant dramatic increase in prevalence of allergic and metabolic diseases is part of a modern epidemic afflicting technologically advanced societies. While clinical evidence points to clear associations between various metabolic factors and atopic disease, there is still a very limited understanding of the mechanisms that link the two. Dysregulation of central metabolism in metabolic syndrome, obesity, diabetes, and dyslipidemia has a systemic impact on multiple tissues and organs, including cells of the epithelial barrier. While much of epithelial research in allergy has focused on the immune-driven processes, a growing number of recent studies have begun to elucidate the role of metabolic components of disease. This review will revisit clinical evidence for the relationship between metabolic and allergic diseases, as well as discuss potential mechanisms driving metabolic dysfunction of the epithelial barrier. Among them, novel studies highlight links between dysregulation of the insulin pathway, glucose metabolism, and loss of epithelial differentiation in asthma. Studies of mitochondrial structure and bioenergetics in lean and obese asthmatic phenotypes recently came to light to provide a novel framework linking changes in tricarboxylic acid cycle and oxidative phosphorylation with arginine metabolism and nitric oxide bioavailability. New research established connections between arachidonate metabolism, autophagy, and airway disease, as well as systemic dyslipidemia in atopic dermatitis and ceramide changes in the epidermis. Taken together, studies of metabolism have a great potential to open doors to a new class of therapeutic strategies, better characterization of disease endotypes, as well as enable a systems biology approach to mechanisms of allergic disease.


Subject(s)
Disease Susceptibility , Energy Metabolism , Epithelial Cells/metabolism , Homeostasis , Hypersensitivity/etiology , Hypersensitivity/metabolism , Animals , Biomarkers , Diabetes Mellitus/metabolism , Humans , Insulin Resistance , Metabolic Networks and Pathways , Mitochondria , Obesity/complications , Obesity/etiology , Obesity/metabolism , Signal Transduction
4.
Am J Respir Cell Mol Biol ; 63(2): 244-254, 2020 08.
Article in English | MEDLINE | ID: mdl-32275835

ABSTRACT

Delayed lung repair leads to alveolopleural fistulae, which are a major cause of morbidity after lung resections. We have reported that intrapleural hypercapnia is associated with delayed lung repair after lung resection. Here, we provide new evidence that hypercapnia delays wound closure of both large airway and alveolar epithelial cell monolayers because of inhibition of epithelial cell migration. Cell migration and airway epithelial wound closure were dependent on Rac1-GTPase activation, which was suppressed by hypercapnia directly through the upregulation of AMP kinase and indirectly through inhibition of injury-induced NF-κB-mediated CXCL12 (pleural CXC motif chemokine 12) release, respectively. Both these pathways were independently suppressed, because dominant negative AMP kinase rescued the effects of hypercapnia on Rac1-GTPase in uninjured resting cells, whereas proteasomal inhibition reversed the NF-κB-mediated CXCL12 release during injury. Constitutive overexpression of Rac1-GTPase rescued the effects of hypercapnia on both pathways as well as on wound healing. Similarly, exogenous recombinant CXCL12 reversed the effects of hypercapnia through Rac1-GTPase activation by its receptor, CXCR4. Moreover, CXCL12 transgenic murine recipients of orthotopic tracheal transplantation were protected from hypercapnia-induced inhibition of tracheal epithelial cell migration and wound repair. In patients undergoing lobectomy, we found inverse correlation between intrapleural carbon dioxide and pleural CXCL12 levels as well as between CXCL12 levels and alveolopleural leak. Accordingly, we provide first evidence that high carbon dioxide levels impair lung repair by inhibiting epithelial cell migration through two distinct pathways, which can be restored by recombinant CXCL12.


Subject(s)
Carbon Dioxide/adverse effects , Lung Injury/physiopathology , Lung/drug effects , Wound Healing/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Animals , Cell Movement/drug effects , Chemokine CXCL12/metabolism , Female , Humans , Hypercapnia/metabolism , Lung/metabolism , Lung Injury/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle Aged , NF-kappa B/metabolism , Receptors, CXCR4/metabolism , Signal Transduction/drug effects
5.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1280-L1281, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32432918

ABSTRACT

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections , Estrogens/pharmacology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Epithelial Cells/drug effects , Epithelial Cells/virology , Estrogens/metabolism , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Respiratory System/drug effects , Respiratory System/metabolism , SARS-CoV-2
7.
J Immunol ; 198(12): 4868-4878, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28476932

ABSTRACT

Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated nonredundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow-derived mast cells and bone marrow-derived basophils (BMBs) at rest, upon an adaptive-type activation (IgE cross-linking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that bone marrow-derived mast cells and BMBs shared specific activation-associated transcriptional signatures but differed in other signatures both between cell type and between activation mode. In bone marrow-derived mast cells, IgE cross-linking upregulated 785 genes, including Egr2, Ccl1, and Fxyd6, whereas IL-33 stimulation induced 823 genes, including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33-activated transcriptome was enriched in genes commonly altered by NF-κB in response to TNF, by IL-6 via STAT3, and in response to IFN-γ. Furthermore, BMBs activated via IgE cross-linking selectively induced immune response genes Ccl1, Il3, and Il2 compared with IL-33-stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.


Subject(s)
Basophils/immunology , Computational Biology , Mast Cells/immunology , Transcription, Genetic , Allergens/metabolism , Animals , Basophils/metabolism , Bone Marrow Cells/immunology , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Gene Regulatory Networks , Immunoglobulin E/chemistry , Immunoglobulin E/immunology , Interleukin-33/pharmacology , Interleukins/genetics , Interleukins/metabolism , Mast Cells/metabolism , Mice , Receptors, IgE/chemistry , Receptors, IgE/immunology , Tissue Array Analysis
8.
J Immunol ; 197(9): 3445-3453, 2016 11 01.
Article in English | MEDLINE | ID: mdl-27683753

ABSTRACT

Eosinophils are important in the pathogenesis of many diseases, including asthma, eosinophilic esophagitis, and eczema. Whereas IL-5 is crucial for supporting mature eosinophils (EoMs), the signals that support earlier eosinophil lineage events are less defined. The IL-33R, ST2, is expressed on several inflammatory cells, including eosinophils, and is best characterized for its role during the initiation of allergic responses in peripheral tissues. Recently, ST2 expression was described on hematopoietic progenitor subsets, where its function remains controversial. Our findings demonstrate that IL-33 is required for basal eosinophil homeostasis, because both IL-33- and ST2-deficient mice exhibited diminished peripheral blood eosinophil numbers at baseline. Exogenous IL-33 administration increased EoMs in both the bone marrow and the periphery in wild-type and IL-33-deficient, but not ST2-deficient, mice. Systemic IL-5 was also increased under this treatment, and blocking IL-5 with a neutralizing Ab ablated the IL-33-induced EoM expansion. The homeostatic hypereosinophilia seen in IL-5-transgenic mice was significantly lower with ST2 deficiency despite similar elevations in systemic IL-5. Finally, in vitro treatment of bone marrow cells with IL-33, but not IL-5, led to specific early expansion of IL-5Rα-expressing precursor cells. In summary, our findings establish a basal defect in eosinophilopoiesis in IL-33- and ST2-deficient mice and a mechanism whereby IL-33 supports EoMs by driving both systemic IL-5 production and the expansion of IL-5Rα-expressing precursor cells.


Subject(s)
Eosinophils/physiology , Interleukin-1 Receptor-Like 1 Protein/metabolism , Interleukin-33/metabolism , Interleukin-5/metabolism , Neutrophils/physiology , Animals , Bone Marrow Cells/physiology , Cell Differentiation , Cell Lineage , Cells, Cultured , Gene Expression Regulation , Hematopoiesis , Homeostasis , Humans , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-33/genetics , Interleukin-5/genetics , Interleukin-5 Receptor alpha Subunit/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout
9.
J Allergy Clin Immunol ; 139(6): 1752-1761, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28583447

ABSTRACT

Epithelial barriers of the skin, gastrointestinal tract, and airway serve common critical functions, such as maintaining a physical barrier against environmental insults and allergens and providing a tissue interface balancing the communication between the internal and external environments. We now understand that in patients with allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed toward loss of differentiation, reduced junctional integrity, and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in initiation of allergic disease, many important questions remain to be answered regarding mechanisms disrupting normal barrier function. Although our external environment (proteases, allergens, and injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, and circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism, and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction using both systems biology tools and causality-driven laboratory experimentation will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergic patients.


Subject(s)
Epithelium/immunology , Hypersensitivity/immunology , Inflammation/immunology , Animals , Humans
10.
J Allergy Clin Immunol ; 140(3): 720-729, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28238741

ABSTRACT

BACKGROUND: Microparticles (MPs) are submicron-sized shed membrane vesicles released from activated or injured cells and are detectable by flow cytometry. MP levels have been used as biomarkers to evaluate cell injury or activation in patients with pathological conditions. OBJECTIVE: We sought to compare MP types and levels in nasal lavage fluids (NLFs) from controls and patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). METHODS: We collected NLFs from patients with CRSsNP (n = 33), CRSwNP (n = 45), and AERD (n = 31) and control (n = 24) subjects. Standardized flow cytometry methods were used to characterize the following MP types: endothelial MPs, epithelial MPs (epithelial cell adhesion molecule [EpCAM](+)MPs, E-cadherin(+)MPs), platelet MPs (CD31(+)CD41(+)MPs), eosinophil MPs (EGF-like module-containing mucin-like hormone receptor-like 1[EMR1](+)MPs), mast cell MPs (high-affinity IgE receptor [FcεRI](+)c-kit(+)MPs), and basophil MPs (CD203c(+)c-kit(-)MPs). Basophil activation was evaluated by the mean fluorescence intensity of CD203c on basophil MPs. RESULTS: Activated mast cell MPs (CD137(+) FcεRI(+)c-kit(+)MPs) were significantly increased in NLFs of controls compared with NLFs of patients with CRSsNP (2.3-fold; P < .02), CRSwNP (2.3-fold; P < .03), and AERD (7.4-fold; P < .0001). Platelet MPs (3.5-fold; P < .01) and basophil MPs (2.5-fold; P < .05) were increased only in patients with AERD. Mean fluorescence intensity of CD203c on MPs was increased in patients with CRSwNP (P < .002) and AERD (P < .0001), but not in patients with CRSsNP. EpCAM(+)MPs in patients with CRSwNP were no different from control (P = .91) and lower than those in patients with CRSsNP (P < .02) and AERD (P < .002). CONCLUSIONS: Based on released MPs, mast cells, platelets, and basophils were more highly activated in patients with AERD than in patients with CRS. Epithelial injury was lower in patients with CRSwNP than in patients with CRSsNP and AERD. MP analysis may help identify phenotypes of CRS, and in distinguishing AERD from CRSwNP.


Subject(s)
Asthma, Aspirin-Induced/pathology , Cell-Derived Microparticles , Nasal Lavage Fluid/cytology , Nasal Polyps/pathology , Rhinitis/pathology , Sinusitis/pathology , Adult , Biomarkers , Chronic Disease , Female , Humans , Male , Middle Aged
11.
Am J Respir Cell Mol Biol ; 56(2): 191-201, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27668462

ABSTRACT

Previous studies established that attenuating Wnt/ß-catenin signaling limits lung fibrosis in the bleomycin mouse model of this disease, but the contribution of this pathway to distinct lung cell phenotypes relevant to tissue repair and fibrosis remains incompletely understood. Using microarray analysis, we found that bleomycin-injured lungs from mice that lack the Wnt coreceptor low density lipoprotein receptor-related protein 5 (Lrp5) and exhibit reduced fibrosis showed enrichment for pathways related to extracellular matrix processing, immunity, and lymphocyte proliferation, suggesting the contribution of an immune-matrix remodeling axis relevant to fibrosis. Activation of ß-catenin signaling was seen in lung macrophages using the ß-catenin reporter mouse, Axin2+/LacZ. Analysis of lung immune cells by flow cytometry after bleomycin administration revealed that Lrp5-/- lungs contained significantly fewer Siglec Flow alveolar macrophages, a cell type previously implicated as positive effectors of fibrosis. Macrophage-specific deletion of ß-catenin in CD11ccre;ß-cateninflox mice did not prevent development of bleomycin-induced fibrosis but facilitated its resolution by 8 weeks. In a nonresolving model of fibrosis, intratracheal administration of asbestos in Lrp5-/- mice also did not prevent the development of fibrosis but hindered the progression of fibrosis in asbestos-treated Lrp5-/- lungs, phenocopying the findings in bleomycin-treated CD11ccre;ß-cateninflox mice. Activation of ß-catenin signaling using lithium chloride resulted in worsened fibrosis in wild-type mice, further supporting that the effects of loss of Lrp5 are directly mediated by Wnt/ß-catenin signaling. Together, these data suggest that lung myeloid cells are responsive to Lrp5/ß-catenin signaling, leading to differentiation of an alveolar macrophage subtype that antagonizes the resolution of lung fibrosis.


Subject(s)
Low Density Lipoprotein Receptor-Related Protein-5/metabolism , Lung/pathology , Macrophages/metabolism , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Wnt Signaling Pathway , beta Catenin/metabolism , Animals , Bleomycin , Cell Differentiation , Extracellular Matrix/metabolism , Immunity , Macrophage Activation , Macrophages/pathology , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/pathology , Mice, Inbred C57BL , Myeloid Cells/metabolism , Myeloid Cells/pathology , Pulmonary Fibrosis/immunology , Sialic Acid Binding Immunoglobulin-like Lectins/metabolism
12.
J Immunol ; 195(4): 1377-87, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26136426

ABSTRACT

Mast cells are critical in the pathogenesis of allergic disease due to the release of preformed and newly synthesized mediators, yet the mechanisms controlling mast cell activation are not well understood. Members of the tetraspanin family are recently emerging as modulators of FcεRI-mediated mast cell activation; however, mechanistic understanding of their function is currently lacking. The tetraspanin CD151 is a poorly understood member of this family and is specifically induced on mouse and human mast cells upon FcεRI aggregation but its functional effects are unknown. In this study, we show that CD151 deficiency significantly exacerbates the IgE-mediated late phase inflammation in a murine model of passive cutaneous anaphylaxis. Ex vivo, FcεRI stimulation of bone marrow-derived mast cells from CD151(-/-) mice resulted in significantly enhanced expression of proinflammatory cytokines IL-4, IL-13, and TNF-α compared with wild-type controls. However, FcεRI-induced mast cell degranulation was unaffected. At the molecular signaling level, CD151 selectively regulated IgE-induced activation of ERK1/2 and PI3K, associated with cytokine production, but had no effect on the phospholipase Cγ1 signaling, associated with degranulation. Collectively, our data indicate that CD151 exerts negative regulation over IgE-induced late phase responses and cytokine production in mast cells.


Subject(s)
Immunomodulation , Mast Cells/immunology , Mast Cells/metabolism , Receptors, IgE/metabolism , Tetraspanin 24/metabolism , Anaphylaxis/genetics , Anaphylaxis/immunology , Anaphylaxis/metabolism , Animals , Cell Degranulation/genetics , Cell Degranulation/immunology , Cell Differentiation , Cytokines/metabolism , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation , Humans , Hypersensitivity/diagnosis , Hypersensitivity/genetics , Hypersensitivity/immunology , Hypersensitivity/metabolism , Immunoglobulin E/immunology , Immunophenotyping , Inflammation Mediators/metabolism , MAP Kinase Signaling System , Mast Cells/cytology , Mice , Mice, Knockout , Passive Cutaneous Anaphylaxis , Phosphatidylinositol 3-Kinases , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Tetraspanin 24/deficiency , Tetraspanin 24/genetics
13.
Am J Respir Crit Care Med ; 192(6): 682-94, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26067893

ABSTRACT

RATIONALE: The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear. OBJECTIVES: To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues. METHODS: Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay. MEASUREMENTS AND MAIN RESULTS: CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed. CONCLUSIONS: CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.


Subject(s)
Asthma, Aspirin-Induced/immunology , Cytokines/metabolism , Nasal Polyps/immunology , Rhinitis/immunology , Sinusitis/immunology , Adult , Aged , Asthma, Aspirin-Induced/metabolism , Biomarkers/metabolism , Case-Control Studies , Chronic Disease , Enzyme-Linked Immunosorbent Assay , Eosinophils/metabolism , Female , Humans , Immunoassay/methods , Male , Middle Aged , Nasal Lavage Fluid/immunology , Nasal Polyps/metabolism , Real-Time Polymerase Chain Reaction , Rhinitis/complications , Rhinitis/metabolism , Sinusitis/complications , Sinusitis/metabolism
15.
Am J Physiol Lung Cell Mol Physiol ; 307(6): L482-96, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25015974

ABSTRACT

α-Tocopherol blocks responses to allergen challenge in allergic adult mice, but it is not known whether α-tocopherol regulates the development of allergic disease. Development of allergic disease often occurs early in life. In clinical studies and animal models, offspring of allergic mothers have increased responsiveness to allergen challenge. Therefore, we determined whether α-tocopherol blocked development of allergic responses in offspring of allergic female mice. Allergic female mice were supplemented with α-tocopherol starting at mating. The pups from allergic mothers developed allergic lung responses, whereas pups from saline-treated mothers did not respond to the allergen challenge, and α-tocopherol supplementation of allergic female mice resulted in a dose-dependent reduction in eosinophils in the pup bronchoalveolar lavage and lungs after allergen challenge. There was also a reduction in pup lung CD11b(+) dendritic cell subsets that are critical to development of allergic responses, but there was no change in several CD11b(-) dendritic cell subsets. Furthermore, maternal supplementation with α-tocopherol reduced the number of fetal liver CD11b(+) dendritic cells in utero. In the pups, there was reduced allergen-induced lung mRNA expression of IL-4, IL-33, TSLP, CCL11, and CCL24. Cross-fostering pups at the time of birth demonstrated that α-tocopherol had a regulatory function in utero. In conclusion, maternal supplementation with α-tocopherol reduced fetal development of subsets of dendritic cells that are critical for allergic responses and reduced development of allergic responses in pups from allergic mothers. These results have implications for supplementation of allergic mothers with α-tocopherol.


Subject(s)
Antioxidants/pharmacology , CD11b Antigen/immunology , CD11c Antigen/immunology , Dendritic Cells/immunology , Dietary Supplements , Hypersensitivity/drug therapy , Prenatal Exposure Delayed Effects/drug therapy , alpha-Tocopherol/pharmacology , Animals , Animals, Newborn , Cytokines/immunology , Dendritic Cells/pathology , Female , Hypersensitivity/immunology , Hypersensitivity/pathology , Mice , Pregnancy , Prenatal Exposure Delayed Effects/immunology , Prenatal Exposure Delayed Effects/pathology
16.
J Immunol ; 188(2): 874-84, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22156494

ABSTRACT

It is reported that PTP1B limits cytokine signaling in vitro. However, PTP1B's function during inflammation in vivo is not known. In this report, we determined whether PTP1B deficiency affects allergic inflammation in vivo. Briefly, lungs of OVA-challenged PTP1B(-/-) mice had elevated numbers of eosinophils and eosinophil progenitors at 6 h after one OVA challenge and at 24 h after a third OVA challenge as compared with OVA-challenged wild-type mice. There was also an increase in numbers of CD11b(+)SiglecF(+)CD34(+)IL-5Rα(+) eosinophil progenitors in the bone marrow, peripheral blood, and spleens of OVA-challenged PTP1B(-/-) mice. Intravital microscopy revealed that, in OVA-challenged PTP1B(-/-) mice, blood leukocytes rapidly bound to endothelium (5-30 min), whereas, in wild-type mice, blood leukocytes bound to endothelium at the expected 6-18 h. Consistent with early recruitment of leukocytes, lung eotaxin and Th2 cytokine levels were elevated early in the PTP1B(-/-) mice. Interestingly, spleen leukocytes from PTP1B(-/-) mice exhibited an increased chemotaxis, chemokinesis, and transendothelial migration in vitro. In summary, PTP1B functions as a critical negative regulator to limit allergic responses.


Subject(s)
Chemotaxis, Leukocyte/immunology , Down-Regulation/immunology , Hematopoiesis/immunology , Inflammation Mediators/physiology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/deficiency , Up-Regulation/immunology , Allergens/toxicity , Animals , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Cell Line , Chemokines/biosynthesis , Chemotaxis, Leukocyte/genetics , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Down-Regulation/genetics , Eosinophils/immunology , Eosinophils/pathology , Female , Hematopoiesis/genetics , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Ovalbumin/toxicity , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Receptors, Chemokine/biosynthesis , Th2 Cells/immunology , Th2 Cells/metabolism , Th2 Cells/pathology , Up-Regulation/genetics
18.
J Leukoc Biol ; 116(2): 288-296, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-38700084

ABSTRACT

Eosinophils, recognized for their immune and remodeling functions and participation in allergic inflammation, have recently garnered attention due to their impact on host metabolism, especially in the regulation of adipose tissue. Eosinophils are now known for their role in adipocyte beiging, adipokine secretion, and adipose tissue inflammation. This intricate interaction involves complex immune and metabolic processes, carrying significant implications for systemic metabolic health. Importantly, the interplay between eosinophils and adipocytes is bidirectional, revealing the dynamic nature of the immune-metabolic axis in adipose tissue. While the homeostatic regulatory role of eosinophils in adipose tissue is appreciated, this relationship in the context of obesity or allergic inflammation is much less understood. Mechanistic details of eosinophil-adipose interactions, especially the direct regulation of adipocytes by eosinophils, are also lacking. Another poorly understood aspect is the metabolism of the eosinophils themselves, encompassing metabolic shifts during eosinophil subset transitions in different tissue microenvironments, along with potential effects of host metabolism on the programming of eosinophil hematopoiesis and the resulting plasticity. This review consolidates recent research in this emerging and fascinating frontier of eosinophil investigation, identifying unexplored areas and presenting innovative perspectives on eosinophil biology in the context of metabolic disorders and associated health conditions, including asthma.


Subject(s)
Asthma , Eosinophils , Metabolic Diseases , Humans , Eosinophils/metabolism , Eosinophils/immunology , Asthma/metabolism , Asthma/immunology , Asthma/pathology , Animals , Metabolic Diseases/metabolism , Metabolic Diseases/immunology , Metabolic Diseases/pathology , Adipose Tissue/metabolism , Adipose Tissue/immunology , Adipocytes/metabolism
19.
bioRxiv ; 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-39026695

ABSTRACT

Although childhood asthma is in part an airway epithelial disorder, the development of the airway epithelium in asthma is not understood. We sought to characterize airway epithelial developmental phenotypes in those with and without recurrent wheeze and the impact of infant infection with respiratory syncytial virus (RSV). Nasal airway epithelial cells (NAECs) were collected at age 2-3 years from an a priori designed nested birth cohort of children from four mutually exclusive groups of wheezers/non-wheezers and RSV-infected/uninfected in the first year of life. NAECs were cultured in air-liquid interface differentiation conditions followed by a combined analysis of single cell RNA sequencing (scRNA-seq) and in vitro infection with respiratory syncytial virus (RSV). NAECs from children with a wheeze phenotype were characterized by abnormal differentiation and basal cell activation of developmental pathways, plasticity in precursor differentiation and a delayed onset of maturation. NAECs from children with wheeze also had increased diversity of currently known RSV receptors and blunted anti-viral immune responses to in vitro infection. The most dramatic changes in differentiation of cultured epithelium were observed in NAECs derived from children that had both wheeze and RSV in the first year of life. Together this suggests that airway epithelium in children with wheeze is developmentally reprogrammed and characterized by increased barrier permeability, decreased antiviral response, and increased RSV receptors, which may predispose to and amplify the effects of RSV infection in infancy and susceptibility to other asthma risk factors that interact with the airway mucosa. SUMMARY: Nasal airway epithelial cells from children with wheeze are characterized by altered development and increased susceptibility to RSV infection.

20.
J Leukoc Biol ; 2024 May 30.
Article in English | MEDLINE | ID: mdl-38814679

ABSTRACT

Neutrophils and eosinophils share common hematopoietic precursors and usually diverge into distinct lineages with unique markers before being released from their hematopoietic site, which is the bone marrow (BM). However, previous studies identified an immature Ly6g(+) Il-5Rα(+) neutrophil population in mouse BM, expressing both neutrophil and eosinophil markers suggesting hematopoietic flexibility. Moreover, others have reported neutrophil populations expressing eosinophil-specific cell surface markers in tissues and altered disease states, confusing the field regarding eosinophil origins, function, and classification. Despite these reports, it is still unclear whether hematopoietic flexibility exists in human granulocytes. To answer this, we utilized single-cell RNA sequencing (scRNA-seq) and CITE-seq to profile human BM and circulating neutrophils and eosinophils at different stages of differentiation and determine whether neutrophil plasticity plays role in asthmatic inflammation. We show that immature metamyelocyte neutrophils in humans expand during severe asthmatic inflammation and express both neutrophil and eosinophil markers. We also show an increase in tri-lobed eosinophils with mixed neutrophil and eosinophil markers in allergic asthma and that IL-5 promotes differentiation of immature blood neutrophils into tri-lobed eosinophilic phenotypes suggesting a mechanism of emergency granulopoiesis to promote myeloid inflammatory or remodeling response in patients with chronic asthma. By providing insights into unexpectedly flexible granulocyte biology and demonstrating emergency hematopoiesis in asthma, our results highlight the importance of granulocyte plasticity in eosinophil development and allergic diseases.

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