Advances and Evolving Concepts in Allergic Asthma

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.

Download Full-text

Selective deletion of SHIP-1 in hematopoietic cells in mice leads to severe lung inflammation involving ILC2 cells

Scientific Reports ◽

10.1038/s41598-021-88677-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xujun Ye ◽

Fengrui Zhang ◽

Li Zhou ◽

Yadong Wei ◽

Li Zhang ◽

...

Keyword(s):

Lung Inflammation ◽

Airway Remodeling ◽

Pulmonary Inflammation ◽

Hematopoietic Cells ◽

Cell Lineage ◽

Allergic Inflammation ◽

Cell Types ◽

Lymphoid Cells ◽

Whole Body

AbstractSrc homology 2 domain–containing inositol 5-phosphatase 1 (SHIP-1) regulates the intracellular levels of phosphotidylinositol-3, 4, 5-trisphosphate, a phosphoinositide 3–kinase (PI3K) product. Emerging evidence suggests that the PI3K pathway is involved in allergic inflammation in the lung. Germline or induced whole-body deletion of SHIP-1 in mice led to spontaneous type 2-dominated pulmonary inflammation, demonstrating that SHIP-1 is essential for lung homeostasis. However, the mechanisms by which SHIP-1 regulates lung inflammation and the responsible cell types are still unclear. Deletion of SHIP-1 selectively in B cells, T cells, dendritic cells (DC) or macrophages did not lead to spontaneous allergic inflammation in mice, suggesting that innate immune cells, particularly group 2 innate lymphoid cells (ILC2 cells) may play an important role in this process. We tested this idea using mice with deletion of SHIP-1 in the hematopoietic cell lineage and examined the changes in ILC2 cells. Conditional deletion of SHIP-1 in hematopoietic cells in Tek-Cre/SHIP-1 mice resulted in spontaneous pulmonary inflammation with features of type 2 immune responses and airway remodeling like those seen in mice with global deletion of SHIP-1. Furthermore, when compared to wild-type control mice, Tek-Cre/SHIP-1 mice displayed a significant increase in the number of IL-5/IL-13 producing ILC2 cells in the lung at baseline and after stimulation by allergen Papain. These findings provide some hints that PI3K signaling may play a role in ILC2 cell development at baseline and in response to allergen stimulation. SHIP-1 is required for maintaining lung homeostasis potentially by restraining ILC2 cells and type 2 inflammation.

Download Full-text

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.

Download Full-text

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.649520 ◽

2021 ◽

Vol 12 ◽

Author(s):

Charu Rajput ◽

Mingyuan Han ◽

Tomoko Ishikawa ◽

Jing Lei ◽

Adam M. Goldsmith ◽

...

Keyword(s):

Mrna Expression ◽

Airway Inflammation ◽

Airway Epithelial Cells ◽

Lymphoid Cells ◽

Airway Epithelial ◽

Eosinophilic Inflammation ◽

Asthma Exacerbations ◽

Rhinovirus C ◽

Type 2 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.

Download Full-text

Pulmonary neuroendocrine cells amplify allergic asthma responses

Science ◽

10.1126/science.aan8546 ◽

2018 ◽

Vol 360 (6393) ◽

pp. eaan8546 ◽

Cited By ~ 89

Author(s):

Pengfei Sui ◽

Darin L. Wiesner ◽

Jinhao Xu ◽

Yan Zhang ◽

Jinwoo Lee ◽

...

Keyword(s):

Allergic Asthma ◽

Goblet Cell ◽

Airway Epithelial Cells ◽

Lymphoid Cells ◽

Neuroendocrine Cells ◽

Airway Epithelial ◽

Branch Points ◽

Cell Hyperplasia ◽

Pulmonary Neuroendocrine Cells ◽

Group 2

Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1-mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1-mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.

Download Full-text

Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

10.1101/2021.06.07.447230 ◽

2021 ◽

Author(s):

Manuel van Gijsel-Bonnello ◽

Nicola J Darling ◽

Laura McDonald ◽

Mairi Sime ◽

Jonathan Clark ◽

...

Keyword(s):

Mast Cells ◽

Allergic Asthma ◽

Immune Cells ◽

Immune Cell ◽

Immunoglobulin E ◽

Therapeutic Potential ◽

Lymphoid Cells ◽

Immune Cell Infiltration ◽

Pharmacokinetic Properties

Interleukin-13 (IL-13) and other Th2 cytokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation in allergic asthma, and are produced when immune cells, such as type 2 innate lymphoid cells (ILC2s) and mast cells are stimulated with IL-33. Here, we report that the IL-33-dependent secretion of IL-13 from ILC2s is prevented by inhibition of the salt-inducible kinases (SIKs), as we have shown previously in mast cells (Darling NJ et al., 2021, J. Biol. Chem. doi: 10.1016/j.jbc.2021.100428). We also report that a new SIK inhibitor with improved pharmacokinetic properties suppresses the recruitment of eosinophils to the lungs and serum immunoglobulin E (IgE) levels in the Alternaria alternata-induced model of allergic asthma. Our results suggest that drugs targeting SIK isoforms may have therapeutic potential for the treatment of asthma.

Download Full-text

Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Nature Communications ◽

10.1038/s41467-021-24853-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ian T. Stancil ◽

Jacob E. Michalski ◽

Duncan Davis-Hall ◽

Hong Wei Chu ◽

Jin-Ah Park ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Airway Epithelium ◽

Cell Types ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Airway Epithelia ◽

Chronic Lung Diseases ◽

Distal Airway ◽

Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

Download Full-text

Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons

Pathogens ◽

10.3390/pathogens10020149 ◽

2021 ◽

Vol 10 (2) ◽

pp. 149

Author(s):

Sreekumar Othumpangat ◽

William G. Lindsley ◽

Donald H. Beezhold ◽

Michael L. Kashon ◽

Carmen N. Burrell ◽

...

Keyword(s):

Healthy Volunteers ◽

Influenza A ◽

Influenza Infection ◽

Cell Types ◽

Airway Epithelial Cells ◽

Differentially Expressed ◽

Influenza B ◽

Airway Epithelial ◽

Monocyte Chemoattractant Protein 1 ◽

Novel Approach

MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression.

Download Full-text

Differential expression of ORCC and CFTR induced by low temperature in CF airway epithelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.1995.268.1.c243 ◽

1995 ◽

Vol 268 (1) ◽

pp. C243-C251 ◽

Cited By ~ 37

Author(s):

M. E. Egan ◽

E. M. Schwiebert ◽

W. B. Guggino

Keyword(s):

Cystic Fibrosis ◽

Epithelial Cells ◽

Incubation Temperature ◽

Cell Types ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Channel Activity ◽

Patch Clamp Recording ◽

Cl Channel ◽

Channel Expression

When nonepithelial cell types expressing the delta F508-cystic fibrosis transmembrane conductance regulator (CFTR) mutation are grown at reduced temperatures, the mutant protein can be properly processed. The effect of low temperatures on Cl- channel activity in airway epithelial cells that endogenously express the delta F508-CFTR mutation has not been investigated. Therefore, we examined the effect of incubation temperature on both CFTR and outwardly rectifying Cl- channel (ORCC) activity in normal, in cystic fibrosis (CF)-affected, and in wild-type CFTR-complemented CF airway epithelia with use of a combination of inside-out and whole cell patch-clamp recording, 36Cl- efflux assays, and immunocytochemistry. We report that incubation of CF-affected airway epithelial cells at 25-27 degrees C is associated with the appearance of a protein kinase A-stimulated CFTR-like Cl- conductance. In addition to the appearance of CFTR Cl- channel activity, there is, however, a decrease in the number of active ORCC when cells are grown at 25-27 degrees C, suggesting that the decrease in incubation temperature may be associated with multiple alterations in ion channel expression and/or regulation in airway epithelial cells.

Download Full-text