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Molecular Mechanisms of Asthma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 55648

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Special Issue Editors

Dr. Georgina Xanthou

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Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11547 Athens, Greece
Interests: immune regulation; allergy; asthma; T cell responses; cytokines; regulatory T cells
Special Issues, Collections and Topics in MDPI journals

Dr. Maria Semitekolou

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Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
Interests: allergic asthma; dendritic cells; activin-A; immune tolerance; lung cancer

Special Issue Information

Dear Colleagues,

Allergic asthma represents a chronic inflammatory airways disease that is characterized by symptoms of wheezing, dyspnea, coughing, and reversible airflow obstruction and associated with airway hyperresponsiveness to innocuous environmental allergens. It affects over 300 million people worldwide and its prevalence has increased in the last decades, especially among children. Asthma encompasses distinct groups of patients with varying features or phenotypes. Notably, a significant cohort of asthmatics exhibit severe disease exacerbations which are poorly controlled by current therapeutic regimes. These patients denote 50% of total healthcare costs, rendering severe asthma (SA) a crucial health and socio-economic burden worldwide.

The aim of this Special Issue is to discuss the molecular and cellular mechanisms that underlie the pathophysiology of allergic asthma with a special focus on immune responses. Original articles and review papers that will be accepted include: (a) those that address the distinct asthma endotypes and characterize SA immunopathogenesis and (b) those that explore the role of immune cells, and more specifically, dendritic cells and Th cells in disease initiation and propagation. Other themes that will be discussed include the contribution of the airway epithelium and innate immune cells, including innate lymphoid cells, in asthma pathogenesis. An integral part of the Special Issue will focus on the molecular mechanisms underlying asthma, and in this context, the effects of alterations in immunometabolic pathways and in immune response genes/immunogenetics will be explored. Finally, an overview of the current developments in therapeutic approaches targeting SA is invited to complete the Special Issue.

Dr. Georgina Xanthou
Dr. Maria Semitekolou
Guest Editors

Manuscript Submission Information

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Keywords

Asthma
Immune response
Dendritic cells
T cells
Airway epithelium
Immunogenetics
Immunometabolism
Innate immune mechanisms
Therapeutic modalities

Published Papers (11 papers)

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Research

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20 pages, 9530 KiB

Open AccessArticle

Fms-Like Tyrosine Kinase 3-Independent Dendritic Cells Are Major Mediators of Th2 Immune Responses in Allergen-Induced Asthmatic Mice

by Sang Chul Park, Dahee Shim, Hongmin Kim, Yeeun Bak, Da Yeon Choi, Joo-Heon Yoon, Chang-Hoon Kim and Sung Jae Shin

Int. J. Mol. Sci. 2020, 21(24), 9508; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249508 - 14 Dec 2020

Cited by 5 | Viewed by 3232

Abstract

Dendritic cells (DCs) are the main mediators of Th2 immune responses in allergic asthma, and Fms-like tyrosine kinase 3 ligand (Flt3L) is an important growth factor for the development and homeostasis of DCs. This study identified the DC populations that primarily cause the initiation and development of allergic lung inflammation using Fms-like tyrosine kinase 3 (Flt3) knockout (KO) mice with allergen-induced allergic asthma. We observed type 2 allergic lung inflammation with goblet cell hyperplasia in Flt3 KO mice, despite a significant reduction in total DCs, particularly CD103⁺ DCs, which was barely detected. In addition, bone marrow-derived dendritic cells (BMDCs) from Flt3 KO mice directed Th2 immune responses in vitro, and the adoptive transfer of these BMDCs exacerbated allergic asthma with more marked Th2 responses than that of BMDCs from wild-type (WT) mice. Furthermore, we found that Flt3L regulated the in vitro expression of OX40 ligand (OX40L) in DCs, which is correlated with DC phenotype in in vivo models. In conclusion, we revealed that Flt3-independent CD11b⁺ DCs direct Th2 responses with the elevated OX40L and are the primary cause of allergic asthma. Our findings suggest that Flt3 is required to control type 2 allergic inflammation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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15 pages, 4332 KiB

Open AccessArticle

Lung Regulatory T Cells Express Adiponectin Receptor 1: Modulation by Obesity and Airway Allergic Inflammation

by Patricia Ramos-Ramírez, Carina Malmhäll, Kristina Johansson, Mikael Adner, Jan Lötvall and Apostolos Bossios

Int. J. Mol. Sci. 2020, 21(23), 8990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238990 - 26 Nov 2020

Cited by 14 | Viewed by 2953

Abstract

Regulatory T cells (Tregs) decrease in the adipose tissue upon weight gain, contributing to persistent low-grade inflammation in obesity. We previously showed that adipose tissue Tregs express the adiponectin receptor 1 (AdipoR1); however, the expression in lung Tregs is still unknown. Here, we aimed to determine whether Helios⁺ and Helios⁻ Treg subsets expressed AdipoR1 in the lungs of obese mice and whether different obesity grades affected the expression upon allergic lung inflammation. For diet-induced obesity (DIO), mice were fed a high-fat diet (HFD) for up to 15 weeks (overweight), 21 weeks (obesity), and 26 weeks (morbid obesity). Overweight and morbidly obese mice were sensitized and challenged with ovalbumin (OVA) to induce allergic lung inflammation. The AdipoR1 expression was reduced significantly in the lung Helios⁺ and Helios⁻ Tregs of obese mice compared with lean mice. Airway allergic inflammation showed reduced AdipoR1 expression in lung Foxp3⁺ Tregs. Obesity significantly exacerbated the eosinophilic airway inflammation and reduced the number of Helios⁺ Tregs in lung and adipose tissue in the obesity-associated asthma model. Upon further weight gain, AdipoR1-expressing Tregs in the lungs of allergic mice were increased, whereas AdipoR1-expressing Tregs in adipose tissue were reduced. These data suggest that obesity-associated adipose tissue inflammation may exacerbate allergic inflammation by downregulating the AdipoR1⁺ Tregs in the lungs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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16 pages, 1324 KiB

Open AccessArticle

Whole Transcriptome Analysis of Myeloid Dendritic Cells Reveals Distinct Genetic Regulation in Patients with Allergies

by Kijeong Lee, Mi-Ryung Han, Ji Woo Yeon, Byoungjae Kim and Tae Hoon Kim

Int. J. Mol. Sci. 2020, 21(22), 8640; https://doi.org/10.3390/ijms21228640 - 16 Nov 2020

Cited by 7 | Viewed by 2118

Abstract

Dendritic cells (DCs) play critical roles in atopic diseases, orchestrating both innate and adaptive immune systems. Nevertheless, limited information is available regarding the mechanism through which DCs induce hyperresponsiveness in patients with allergies. This study aims to reveal novel genetic alterations and future therapeutic target molecules in the DCs from patients with allergies using whole transcriptome sequencing. Transcriptome sequencing of human BDCA-3+/CD11c+ DCs sorted from peripheral blood monocytes obtained from six patients with allergies and four healthy controls was conducted. Gene expression profile data were analyzed, and an ingenuity pathway analysis was performed. A total of 1638 differentially expressed genes were identified at p-values < 0.05, with 11 genes showing a log2-fold change ≥1.5. The top gene network was associated with cell death/survival and organismal injury/abnormality. In validation experiments, amphiregulin (AREG) showed consistent results with transcriptome sequencing data, with increased mRNA expression in THP-1-derived DCs after Der p 1 stimulation and higher protein expression in myeloid DCs obtained from patients with allergies. This study suggests an alteration in the expression of DCs in patients with allergies, proposing related altered functions and intracellular mechanisms. Notably, AREG might play a crucial role in DCs by inducing the Th2 immune response. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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18 pages, 14538 KiB

Open AccessArticle

GM-CSF and IL-33 Orchestrate Polynucleation and Polyploidy of Resident Murine Alveolar Macrophages in a Murine Model of Allergic Asthma

by Katharina M. Quell, Kuheli Dutta, Ülkü R. Korkmaz, Larissa Nogueira de Almeida, Tillman Vollbrandt, Peter König, Ian Lewkowich, George S. Deepe, Admar Verschoor, Jörg Köhl and Yves Laumonnier

Int. J. Mol. Sci. 2020, 21(20), 7487; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207487 - 11 Oct 2020

Cited by 4 | Viewed by 3184

Abstract

Allergic asthma is a chronical pulmonary disease with high prevalence. It manifests as a maladaptive immune response to common airborne allergens and is characterized by airway hyperresponsiveness, eosinophilia, type 2 cytokine-associated inflammation, and mucus overproduction. Alveolar macrophages (AMs), although contributing to lung homeostasis and tolerance to allergens at steady state, have attracted less attention compared to professional antigen-presenting and adaptive immune cells in their contributions. Using an acute model of house dust mite-driven allergic asthma in mice, we showed that a fraction of resident tissue-associated AMs, while polarizing to the alternatively activated M2 phenotype, exhibited signs of polynucleation and polyploidy. Mechanistically, in vitro assays showed that only Granulocyte-Macrophage Colony Stimulating Factor and interleukins IL-13 and IL-33, but not IL-4 or IL-5, participate in the establishment of this phenotype, which resulted from division defects and not cell-cell fusion as shown by microscopy. Intriguingly, mRNA analysis of AMs isolated from allergic asthmatic lungs failed to show changes in the expression of genes involved in DNA damage control except for MafB. Altogether, our data support the idea that upon allergic inflammation, AMs undergo DNA damage-induced stresses, which may provide new unconventional therapeutical approaches to treat allergic asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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16 pages, 5923 KiB

Open AccessArticle

Inhalations with Brine Solution from the ‘Wieliczka’ Salt Mine Diminish Airway Hyperreactivity and Inflammation in a Murine Model of Non-Atopic Asthma

by Dominika Zając, Ewelina Russjan, Magdalena Kostrzon and Katarzyna Kaczyńska

Int. J. Mol. Sci. 2020, 21(13), 4798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134798 - 07 Jul 2020

Cited by 6 | Viewed by 2379

Abstract

Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features underlying their action on the respiratory system have been explored. The aim of the present study was to elucidate the mechanism of the beneficial action of inhalations of brine solution from the ‘Wieliczka’ Salt Mine, a Polish health resort, in a murine model of non-atopic asthma. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by an intratracheal challenge of cognate hapten. All animals underwent 12 inhalation sessions with brine solution, pure water or physiological saline. Control mice were not inhaled. We found that brine inhalations reduced, as compared to non-inhaled mice, the typical asthma-related symptoms, like airway hyperreactivity (AHR), the infiltration of pro-inflammatory cells into the bronchial tree, and the inflammation of the airways at the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6. The level of the anti-inflammatory IL-10 was elevated in brine-inhaled mice. Inhalations with pure water increased AHR, whereas saline had no influence, either on AHR or cytokine concentrations. These observations indicate that inhalations with a brine solution from the ‘Wieliczka’ Salt Mine diminish the asthma-related symptoms, mostly by reducing the inflammatory status and by decreasing AHR. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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Review

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27 pages, 767 KiB

Open AccessReview

Adiponectin and Asthma: Knowns, Unknowns and Controversies

by Marina Ruxandra Otelea, Oana Cristina Arghir, Corina Zugravu and Agripina Rascu

Int. J. Mol. Sci. 2021, 22(16), 8971; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168971 - 20 Aug 2021

Cited by 14 | Viewed by 2836

Abstract

Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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23 pages, 1250 KiB

Open AccessReview

Autophagy: A Friend or Foe in Allergic Asthma?

by Efthymia Theofani and Georgina Xanthou

Int. J. Mol. Sci. 2021, 22(12), 6314; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126314 - 12 Jun 2021

Cited by 19 | Viewed by 3420

Abstract

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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14 pages, 308 KiB

Open AccessReview

Genetics and Epigenetics in Asthma

by Polyxeni Ntontsi, Andreas Photiades, Eleftherios Zervas, Georgina Xanthou and Konstantinos Samitas

Int. J. Mol. Sci. 2021, 22(5), 2412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052412 - 27 Feb 2021

Cited by 65 | Viewed by 13303

Abstract

Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes and underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain and predict asthma’s complexity and heterogeneity, and genome-wide association studies (GWAS) quickly became the preferred study method. Several gene markers and loci associated with asthma susceptibility, atopic and childhood-onset asthma were identified during the last few decades. Markers near the ORMDL3/GSDMB genes were associated with childhood-onset asthma, interleukin (IL)33 and IL1RL1 SNPs were associated with atopic asthma, and the Thymic Stromal Lymphopoietin (TSLP) gene was identified as protective against the risk to TH2-asthma. The latest efforts and advances in identifying and decoding asthma susceptibility are focused on epigenetics, heritable characteristics that affect gene expression without altering DNA sequence, with DNA methylation being the most described mechanism. Other less studied epigenetic mechanisms include histone modifications and alterations of miR expression. Recent findings suggest that the DNA methylation pattern is tissue and cell-specific. Several studies attempt to describe DNA methylation of different types of cells and tissues of asthmatic patients that regulate airway remodeling, phagocytosis, and other lung functions in asthma. In this review, we attempt to briefly present the latest advancements in the field of genetics and mainly epigenetics concerning asthma susceptibility. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

29 pages, 1646 KiB

Open AccessReview

The Airway Epithelium—A Central Player in Asthma Pathogenesis

by Jenny Calvén, Elisabeth Ax and Madeleine Rådinger

Int. J. Mol. Sci. 2020, 21(23), 8907; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238907 - 24 Nov 2020

Cited by 46 | Viewed by 10008

Abstract

Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction in response to a wide range of exogenous stimuli. The airway epithelium is the first line of defense and plays an important role in initiating host defense and controlling immune responses. Indeed, increasing evidence indicates a range of abnormalities in various aspects of epithelial barrier function in asthma. A central part of this impairment is a disruption of the airway epithelial layer, allowing inhaled substances to pass more easily into the submucosa where they may interact with immune cells. Furthermore, many of the identified susceptibility genes for asthma are expressed in the airway epithelium. This review focuses on the biology of the airway epithelium in health and its pathobiology in asthma. We will specifically discuss external triggers such as allergens, viruses and alarmins and the effect of type 2 inflammatory responses on airway epithelial function in asthma. We will also discuss epigenetic mechanisms responding to external stimuli on the level of transcriptional and posttranscriptional regulation of gene expression, as well the airway epithelium as a potential treatment target in asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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21 pages, 2999 KiB

Open AccessReview

The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe?

by Odile Poulain-Godefroy, Mélodie Bouté, Julie Carrard, Daniel Alvarez-Simon, Anne Tsicopoulos and Patricia de Nadai

Int. J. Mol. Sci. 2020, 21(22), 8797; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228797 - 20 Nov 2020

Cited by 21 | Viewed by 5468

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has emerged as an important player in asthma control. AhR is responsive to environmental molecules and endogenous or dietary metabolites and regulates innate and adaptive immune responses. Binding of this receptor by different ligands has led to seemingly opposite responses in different asthma models. In this review, we present two sides of the same coin, with the beneficial and deleterious roles of AhR evaluated using known endogenous or exogenous ligands, deficient mice or antagonists. On one hand, AhR has an anti-inflammatory role since its activation in dendritic cells blocks the generation of pro-inflammatory T cells or shifts macrophages toward an anti-inflammatory M2 phenotype. On the other hand, AhR activation by particle-associated polycyclic aromatic hydrocarbons from the environment is pro-inflammatory, inducing mucus hypersecretion, airway remodelling, dysregulation of antigen presenting cells and exacerbates asthma features. Data concerning the role of AhR in cells from asthmatic patients are also reviewed, since AhR could represent a potential target for therapeutic immunomodulation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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16 pages, 1630 KiB

Open AccessReview

Dendritic Cells: Critical Regulators of Allergic Asthma

by Ioannis Morianos and Maria Semitekolou

Int. J. Mol. Sci. 2020, 21(21), 7930; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217930 - 26 Oct 2020

Cited by 35 | Viewed by 5708

Abstract

Allergic asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness (AHR), chronic airway inflammation, and excessive T helper (Th) type 2 immune responses against harmless airborne allergens. Dendritic cells (DCs) represent the most potent antigen-presenting cells of the immune system that act as a bridge between innate and adaptive immunity. Pertinent to allergic asthma, distinct DC subsets are known to play a central role in initiating and maintaining allergen driven Th2 immune responses in the airways. Nevertheless, seminal studies have demonstrated that DCs can also restrain excessive asthmatic responses and thus contribute to the resolution of allergic airway inflammation and the maintenance of pulmonary tolerance. Notably, the transfer of tolerogenic DCs in vivo suppresses Th2 allergic responses and protects or even reverses established allergic airway inflammation. Thus, the identification of novel DC subsets that possess immunoregulatory properties and can efficiently control aberrant asthmatic responses is critical for the re-establishment of tolerance and the amelioration of the asthmatic disease phenotype. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Asthma)

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