Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.

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Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

International Journal of Molecular Sciences ◽

10.3390/ijms22094369 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4369

Author(s):

Corrado Pelaia ◽

Giulia Pelaia ◽

Claudia Crimi ◽

Angelantonio Maglio ◽

Luca Gallelli ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Human Monoclonal Antibody ◽

Airway Epithelial Cells ◽

Lymphoid Cells ◽

Airway Epithelial ◽

Airborne Pollutants ◽

Group 2 ◽

Efficacy Profile ◽

Refractory Asthma

Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and efficacy profile in patients with severe, uncontrolled asthma.

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Allergen protease-induced Gsdmd p40 controls IL-33 secretion

10.21203/rs.3.rs-140435/v1 ◽

2021 ◽

Author(s):

Bing Sun ◽

Bin Wu ◽

Dong Wu ◽

Feng Shao ◽

Yaguang Zhang ◽

...

Keyword(s):

Airway Inflammation ◽

Critical Role ◽

Allergic Airway Inflammation ◽

Airway Epithelial Cells ◽

Allergen Exposure ◽

Lymphoid Cells ◽

House Dust Mites ◽

Airway Epithelial ◽

Group 2 ◽

Inflammatory Caspases

Abstract Interleukin (IL)-33, an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammation, such as that in asthma. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we demonstrated that Gasdermin D (Gsdmd) functions as a conduit for IL-33 secretion following allergen protease exposure. Gsdmd was rapidly cleaved into a functional neo-form, the N-terminal p40 fragment (p40 NT-Gsdmd), in the murine airway epithelium when cells were exposed to allergen proteases from fungi, house dust mites (HDMs), or bacteria. This cleavage event that produces the p40 Gsdmd fragment was independent of inflammatory caspases-1/11, as it could not be inhibited by caspase-1 and caspase-11 deficiency in murine cells. The functional p40 NT-Gsdmd fragment directly contributed to the secretion of both the nuclear full-length form and cytosolic mature form of IL-33. Both Gsdmd deficiency and blockade of the generation of p40 by amino acid mutation or deletion of residues 308–313 (ELRQQ) in the Gsdmd sequence could efficiently prevent IL-33 release in airway epithelial cells. In mice, Gsdmd deficiency prevented IL-33 release and hindered the activation of group 2 innate lymphoid cells (ILC2s), thus alleviating airway inflammation and lung tissue damage after stimulation with HDMs or papain. Our findings uncovered a mechanism of Gsdmd-mediated IL-33 release under allergen exposure and offer insight into Gsdmd cleavage prevention as a potential approach to reduce allergic airway inflammation.

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Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2020.05.004 ◽

2020 ◽

Vol 146 (1) ◽

pp. 80-88.e8 ◽

Cited By ~ 48

Author(s):

Hiroki Kimura ◽

Dave Francisco ◽

Michelle Conway ◽

Fernando D. Martinez ◽

Donata Vercelli ◽

...

Keyword(s):

Epithelial Cells ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Type 2 Inflammation

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Advances and Evolving Concepts in Allergic Asthma

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0037-1607981 ◽

2018 ◽

Vol 39 (01) ◽

pp. 064-081 ◽

Cited By ~ 9

Author(s):

Hui-Ying Tung ◽

Evan Li ◽

Cameron Landers ◽

An Nguyen ◽

Farrah Kheradmand ◽

...

Keyword(s):

Allergic Asthma ◽

Immunoglobulin E ◽

Airway Remodeling ◽

Cell Types ◽

Airway Epithelial Cells ◽

Lymphoid Cells ◽

Airway Epithelial ◽

Clotting Factors ◽

Particulate Pollution

AbstractAllergic asthma is a heterogeneous disorder that defies a unanimously acceptable definition, but is generally recognized through its highly characteristic clinical expression of dyspnea and cough accompanied by clinical data that document reversible or exaggerated airway constriction and obstruction. The generally rising prevalence of asthma in highly industrialized societies despite significant therapeutic advances suggests that the fundamental cause(s) of asthma remain poorly understood. Detailed analyses of both the indoor (built) and outdoor environments continue to support the concept that not only inhaled particulates, especially carbon-based particulate pollution, pollens, and fungal elements, but also many noxious gases and chemicals, especially biologically derived byproducts such as proteinases, are essential to asthma pathogenesis. Phthalates, another common class of chemical pollutant found in the built environment, are emerging as potentially important mediators or attenuators of asthma. Other biological products such as endotoxin have also been confirmed to be protective in both the indoor and outdoor contexts. Proasthmatic factors are believed to activate, and in some instances initiate, pathologic inflammatory cascades through complex interactions with pattern recognition receptors (PRRs) expressed on many cell types, but especially airway epithelial cells. PRRs initiate the release of proallergic cytokines such as interleukin (IL)-33, IL-25, and others that coordinate activation of innate lymphoid cells type 2 (ILC2), T helper type 2 cells, and immunoglobulin E–secreting B cells that together promote additional inflammation and the major airway remodeling events (airway hyperresponsiveness, mucus hypersecretion) that promote airway obstruction. Proteinases, with airway fungi and viruses being potentially important sources, are emerging as critically important initiators of these inflammatory cascades in part through their effects on clotting factors such as fibrinogen. Recent clinical trials have demonstrated that targeting inflammatory pathways orchestrated through IL-4, IL-5, IL-13, and the prostaglandin receptor CRTH2 is potentially highly effective in adult asthma.

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The Significance of Hypothiocyanite Production via the Pendrin/DUOX/Peroxidase Pathway in the Pathogenesis of Asthma

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1054801 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Kenji Izuhara ◽

Shoichi Suzuki ◽

Masahiro Ogawa ◽

Satoshi Nunomura ◽

Yasuhiro Nanri ◽

...

Keyword(s):

Airway Inflammation ◽

Inhaled Corticosteroids ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Apical Side ◽

Asthma Patients ◽

High Doses ◽

Antithyroid Agents ◽

Antiasthma Drugs

Inhaled corticosteroids (ICSs) are used as first-line drugs for asthma, and various novel antiasthma drugs targeting type 2 immune mediators are now under development. However, molecularly targeted drugs are expensive, creating an economic burden on patients. We and others previously found pendrin/SLC26A4 as a downstream molecule of IL-13, a signature type 2 cytokine critical for asthma, and showed its significance in the pathogenesis of asthma using model mice. However, the molecular mechanism of how pendrin causes airway inflammation remained elusive. We have recently demonstrated that hypothiocyanite (OSCN−) produced by the pendrin/DUOX/peroxidase pathway has the potential to cause airway inflammation. Pendrin transports thiocyanate (SCN−) into pulmonary lumens at the apical side. Peroxidases catalyze SCN− and H2O2 generated by DUOX into OSCN−. Low doses of OSCN− activate NF-κB in airway epithelial cells, whereas OSCN− in high doses causes necrosis of the cells, inducing the release of IL-33 and accelerating inflammation. OSCN− production is augmented in asthma model mice and possibly in some asthma patients. Heme peroxidase inhibitors, widely used as antithyroid agents, diminish asthma-like phenotypes in mice, indicating the significance of this pathway. These findings suggest the possibility of repositioning antithyroid agents as antiasthma drugs.

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Migration of Lung Resident Group 2 Innate Lymphoid Cells Link Allergic Lung Inflammation and Liver Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.679509 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laura Mathä ◽

Mónica Romera-Hernández ◽

Catherine A. Steer ◽

Yi Han Yin ◽

Mona Orangi ◽

...

Keyword(s):

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Eosinophilic Inflammation ◽

Allergic Lung Inflammation ◽

Pre Treatment ◽

Group 2 ◽

Resident Group ◽

Type 2 Inflammation

Group 2 innate lymphoid cells (ILC2s) are tissue resident in the lung and activated by inhaled allergens via epithelial-derived alarmins including IL-33. Activated ILC2s proliferate, produce IL-5 and IL-13, and induce eosinophilic inflammation. Here, we report that intranasal IL-33 or the protease allergen papain administration resulted in increased numbers of ILC2s not only in the lung but also in peripheral blood and liver. Analyses of IL-33 treated parabiosis mice showed that the increase in lung ILC2s was due to proliferation of lung resident ILC2s, whereas the increase in liver ILC2s was due to the migration of activated lung ILC2s. Lung-derived ILC2s induced eosinophilic hepatitis and expression of fibrosis-related genes. Intranasal IL-33 pre-treatment also attenuated concanavalin A-induced acute hepatitis and cirrhosis. These results suggest that activated lung resident ILC2s emigrate from the lung, circulate, settle in the liver and promote type 2 inflammation and attenuate type 1 inflammation.

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