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The Molecular and Cellular Basis for Allergies & Asthma
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The Molecular and Cellular Basis for Allergies & Asthma

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 67010

Special Issue Editor

Dr. Cenk Suphioglu

E-Mail Website1 Website2
Guest Editor
NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Waurn Ponds, Victoria 3216, Australia
Interests: aerobiology; allergic asthma; allergy diagnostics; allergy immunotherapy reagents; cytokine signalling; epigenetics; food allergy; inhibitors of allergic reaction; inhibitors of Alzheimer’s disease; neuroscience; nutrition; pollen allergy; thunderstorm asthma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Welcome to this Special Issue of Cells on “Molecular and Cellular Basis for Allergies and Asthma". 

Allergies and Asthma are chronic health conditions that range in frequency and severity from mild to life-threatening symptoms, which vary from person to person. In particular, the importance of allergic asthma gained much international press and attention following Melbourne’s recent deadly thunderstorm asthma epidemic of November 21, 2016, which resulted in 10 deaths and thousands of sufferers seeking emergency medical attention. Although one can suffer from allergies without ever having a previous episode of an asthma attack, it is now known and well accepted that people with certain allergies (grass pollen and fungal spore allergies for example) can be particularly vulnerable to thunderstorm asthma epidemics and thus the importance of research on the molecular and cellular basis for allergies and asthma.

This Special Issue is intended to present latest findings related to the molecular and cellular basis for allergies and asthma, as well as the molecular and cellular links between the two conditions. Original research and review articles on all topics related to molecular and cellular basis for allergies and asthma are invited. I have the pleasure in inviting research scientists and clinicians from all relevant fields to submit their papers for this important and timely Special Issue. Please accept my sincere thanks for choosing to publish in Cells and I look forward to your submissions for this highly interesting, relevant and important Special Issue.

Assoc. Prof. Cenk Suphioglu
Guest Editor

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Keywords

  • Allergens
  • Allergic Asthma
  • Allergic rhinitis
  • Allergy
  • Asthma
  • Atopy
  • B cells
  • Basophils
  • Cellular Allergy
  • Cellular Asthma
  • Dendritic cells
  • Eosinophils
  • Helper T cells
  • Hypersensitivity
  • IgE
  • IL-4
  • IL-5
  • IL-13
  • Mast cells
  • Molecular Allergy
  • Molecular Asthma
  • Regulatory T cells
  • STAT6
  • Th1 cells
  • Th2 cells
  • Thunderstorm Asthma

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Published Papers (11 papers)

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Research

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26 pages, 5615 KiB  
Article
Allergen-Induced C5a/C5aR1 Axis Activation in Pulmonary CD11b+ cDCs Promotes Pulmonary Tolerance through Downregulation of CD40
by Konstantina Antoniou, Fanny Ender, Tillman Vollbrandt, Yves Laumonnier, Franziska Rathmann, Chandrashekhar Pasare, Harinder Singh and Jörg Köhl
Cells 2020, 9(2), 300; https://doi.org/10.3390/cells9020300 - 26 Jan 2020
Cited by 11 | Viewed by 4569
Abstract
Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b+ conventional dendritic cells (cDCs) in the context of house-dust-mite [...] Read more.
Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b+ conventional dendritic cells (cDCs) in the context of house-dust-mite (HDM) exposure. BALB/c mice were intratracheally immunized with an HDM/ovalbumin (OVA) mixture. After 24 h, we detected two CD11b+ cDC populations that could be distinguished on the basis of C5aR1 expression. C5aR1− but not C5aR1+ cDCs strongly induced T cell proliferation of OVA-reactive transgenic CD4+ T cells after re-exposure to antigen in vitro. C5aR1− cDCs expressed higher levels of MHC-II and CD40 than their C5aR1+ counterparts, which correlated directly with a higher frequency of interactions with cognate CD4+ T cells. Priming of OVA-specific T cells by C5aR1+ cDCs could be markedly increased by in vitro blockade of C5aR1 and this was associated with increased CD40 expression. Simultaneous blockade of C5aR1 and CD40L on C5aR1+ cDCs decreased T cell proliferation. Finally, pulsing with OVA-induced C5 production and its cleavage into C5a by both populations of CD11b+ cDCs. Thus, we propose a model in which allergen-induced autocrine C5a generation and subsequent C5aR1 activation in pulmonary CD11b+ cDCs promotes tolerance towards aeroallergens through downregulation of CD40. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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13 pages, 1679 KiB  
Article
Dendritic Cells Expressing MyD88 Molecule Are Necessary and Sufficient for CpG-Mediated Inhibition of IgE Production In Vivo
by Ricardo W. Alberca Custodio, Luciana Mirotti, Eliane Gomes, Fernanda P.B. Nunes, Raquel S. Vieira, Luís Graça, Rafael R. Almeida, Niels O. S. Câmara and Momtchilo Russo
Cells 2019, 8(10), 1165; https://doi.org/10.3390/cells8101165 - 28 Sep 2019
Cited by 9 | Viewed by 3250
Abstract
Elevated levels of immunoglobulin E (IgE) are associated with allergies and other immunological disorders. Sensitization with alum adjuvant favours IgE production while CpG-ODN adjuvant, a synthetic toll-like receptor 9 (TLR9) agonist, inhibits it. The cellular mechanisms underlying in vivo TLR regulation of immunoglobulin [...] Read more.
Elevated levels of immunoglobulin E (IgE) are associated with allergies and other immunological disorders. Sensitization with alum adjuvant favours IgE production while CpG-ODN adjuvant, a synthetic toll-like receptor 9 (TLR9) agonist, inhibits it. The cellular mechanisms underlying in vivo TLR regulation of immunoglobulin production, specially IgE, are still controversial. Specifically, TLR-mediated IgE regulation in vivo is not yet known. In this study we showed that augmented levels of IgE induced by sensitizations to OVA with or without alum adjuvant or with OVA-pulsed dendritic cells (DCs) were inhibited by co-administration of CpG. Notably, CpG-mediated suppression of IgE production required MyD88-expression on DCs but not on B-cells. This finding contrasts with previous in vitro studies reporting regulation of IgE by a direct action of CpG on B cells via MyD88 pathway. In addition, we showed that CpG also inhibited IgE production in a MyD88-dependent manner when sensitization was performed with OVA-pulsed DCs. Finally, CpG signalling through MyD88 pathway was also necessary and sufficient to prevent anaphylactic antibody production involved in active cutaneous anaphylaxis. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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12 pages, 1832 KiB  
Article
Analysis of Allergen-Specific T Cell and IgE Reactivity to Different Preparations of Cow’s Milk-Containing Food Extracts
by Meng Chen, Aaron Sutherland, Giovanni Birrueta, Susan Laubach, Stephanie Leonard, Bjoern Peters and Véronique Schulten
Cells 2019, 8(7), 667; https://doi.org/10.3390/cells8070667 - 2 Jul 2019
Cited by 7 | Viewed by 3792
Abstract
Background: cow’s milk allergy (CM) is among the most common food allergies in young children and is often outgrown by adulthood. Prior to developing a tolerance to CM, a majority of CM-allergic children may tolerate extensively-heated CM. This study aims to characterize the [...] Read more.
Background: cow’s milk allergy (CM) is among the most common food allergies in young children and is often outgrown by adulthood. Prior to developing a tolerance to CM, a majority of CM-allergic children may tolerate extensively-heated CM. This study aims to characterize the IgE- and T cell-reactivity to unheated CM and the progressively more heated CM-containing foods. Methods: CM-containing food extracts from muffin, baked cheese, custard and raw, pasteurized CM commercial extract were tested for skin prick test reactivity, IgE binding and T cell reactivity as assessed by IL-5 and IFNγ production. Results: the skin prick test (SPT) reactivity was significantly decreased to muffin extract compared to raw, pasteurized CM. Both IgE- and T-cell reactivity were readily detectable against food extracts from all forms of CM. Western blot analysis of IgE reactivity revealed variability between extracts that was protein-specific. T cell-reactivity was detected against all four extracts with no significant difference in IL-5 or IFNγ production between them. Conclusion: our data indicate that despite reduced clinical reactivity, extracts from heated CM-containing foods retain immunogenicity when tested in vitro, particularly at the T cell level. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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19 pages, 3079 KiB  
Article
NFκB- and MAP-Kinase Signaling Contribute to the Activation of Murine Myeloid Dendritic Cells by a Flagellin A: Allergen Fusion Protein
by Tobias Moeller, Sonja Wolfheimer, Alexandra Goretzki, Stephan Scheurer and Stefan Schülke
Cells 2019, 8(4), 355; https://doi.org/10.3390/cells8040355 - 15 Apr 2019
Cited by 16 | Viewed by 4900
Abstract
Fusion proteins incorporating the TLR5-ligand flagellin are currently undergoing clinical trials as vaccine candidates for many diseases. We recently reported a flagellin:allergen fusion protein containing the TLR5-ligand flagellin A (FlaA) from Listeria monocytogenes and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) [...] Read more.
Fusion proteins incorporating the TLR5-ligand flagellin are currently undergoing clinical trials as vaccine candidates for many diseases. We recently reported a flagellin:allergen fusion protein containing the TLR5-ligand flagellin A (FlaA) from Listeria monocytogenes and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) to prevent allergic sensitization in an experimental mouse model. This study analyzes the signaling pathways contributing to rFlaA:Betv1-mediated pro- and anti-inflammatory cytokine secretion and cell metabolism in myeloid dendritic cells (mDCs) in vitro. The influence of mammalian target of rapamycin (mTOR)-, NFκB-, and MAP kinase (MAPK)-signaling on cytokine secretion and metabolic activity of bone marrow (BM)-derived mDCs stimulated with rFlaA:Betv1 were investigated by pre-treatment with either mTOR- (rapamycin), NFκB- (dexamethason, BMS-345541, TPCA-1, triptolide, or BAY-11) or MAPK- (SP600125, U0126, or SB202190) inhibitors, respectively. rFlaA:Betv1-mediated IL-10 secretion as well as activation of mDC metabolism, rather than pro-inflammatory cytokine secretion, were inhibited by rapamycin. Inhibition of NFκB-signaling suppressed rFlaA:Betv1-induced IL-12, while inhibition of MAPK-signaling dose-dependently suppressed rFlaA:Betv1-induced IL-10 as well as pro-inflammatory IL-6 and TNF-α production. Notably, with the exception of a partial JNK-dependency, rFlaA:Betv1-mediated effects on mDC metabolism were mostly NFκB- and MAPK-independent. Therefore, MAPK-mediated activation of both NFκB- and mTOR-signaling likely is a key pathway for the production of pro- and anti-inflammatory cytokines by flagellin fusion protein vaccines. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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Review

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14 pages, 1401 KiB  
Review
Progress in the Analysis of Food Allergens through Molecular Biology Approaches
by Mariateresa Volpicella, Claudia Leoni, Maria C.G. Dileo and Luigi R. Ceci
Cells 2019, 8(9), 1073; https://doi.org/10.3390/cells8091073 - 12 Sep 2019
Cited by 26 | Viewed by 5682
Abstract
Food allergies associated with class E immunoglobulins (IgE) are a serious health problem that affects between 1% and 10% of the population of developing countries, with a variability that depends on the geographical area and age range considered. These allergies are caused by [...] Read more.
Food allergies associated with class E immunoglobulins (IgE) are a serious health problem that affects between 1% and 10% of the population of developing countries, with a variability that depends on the geographical area and age range considered. These allergies are caused by a cross-link reaction between a specific food protein (the allergen) and the host IgE. Allergic reactions can range from mild itching to anaphylactic shock and there are no clues to predict the effects of an allergen. Strict avoidance of allergenic food is the only way to avoid possible serious allergic reactions. In the last 30 years a growing number of molecular studies have been conducted to obtain information on the diffusion of food allergens and to establish the structural basis of their allergenicity. At the same time, these studies have also allowed the development of molecular tools (mainly based on synthetic peptides and recombinant allergens) that can be of great help for diagnostic and therapeutic approaches of food allergies. Accordingly, this review focuses on advances in the study of food allergens made possible by molecular technologies and how results and technologies can be integrated for the development of a systematic food molecular allergology. The review may be of interest both to scientists approaching this field of investigation and to physicians who wish to have an update on the progress of research in diagnosis and therapy of food allergies. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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25 pages, 10791 KiB  
Review
Tracing IgE-Producing Cells in Allergic Patients
by Julia Eckl-Dorna, Sergio Villazala-Merino, Nicholas James Campion, Maria Byazrova, Alexander Filatov, Dmitry Kudlay, Antonina Karsonova, Ksenja Riabova, Musa Khaitov, Alexander Karaulov, Verena Niederberger-Leppin and Rudolf Valenta
Cells 2019, 8(9), 994; https://doi.org/10.3390/cells8090994 - 28 Aug 2019
Cited by 39 | Viewed by 7637
Abstract
Immunoglobulin E (IgE) is the key immunoglobulin in the pathogenesis of IgE associated allergic diseases affecting 30% of the world population. Recent data suggest that allergen-specific IgE levels in serum of allergic patients are sustained by two different mechanisms: inducible IgE production through [...] Read more.
Immunoglobulin E (IgE) is the key immunoglobulin in the pathogenesis of IgE associated allergic diseases affecting 30% of the world population. Recent data suggest that allergen-specific IgE levels in serum of allergic patients are sustained by two different mechanisms: inducible IgE production through allergen exposure, and continuous IgE production occurring even in the absence of allergen stimulus that maintains IgE levels. This assumption is supported by two observations. First, allergen exposure induces transient increases of systemic IgE production. Second, reduction in IgE levels upon depletion of IgE from the blood of allergic patients using immunoapheresis is only temporary and IgE levels quickly return to pre-treatment levels even in the absence of allergen exposure. Though IgE production has been observed in the peripheral blood and locally in various human tissues (e.g., nose, lung, spleen, bone marrow), the origin and main sites of IgE production in humans remain unknown. Furthermore, IgE-producing cells in humans have yet to be fully characterized. Capturing IgE-producing cells is challenging not only because current staining technologies are inadequate, but also because the cells are rare, they are difficult to discriminate from cells bearing IgE bound to IgE-receptors, and plasma cells express little IgE on their surface. However, due to the central role in mediating both the early and late phases of allergy, free IgE, IgE-bearing effector cells and IgE-producing cells are important therapeutic targets. Here, we discuss current knowledge and unanswered questions regarding IgE production in allergic patients as well as possible therapeutic approaches targeting IgE. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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24 pages, 1136 KiB  
Review
Advanced Molecular Knowledge of Therapeutic Drugs and Natural Products Focusing on Inflammatory Cytokines in Asthma
by Sheng-Chieh Lin, Li-Shian Shi and Yi-Ling Ye
Cells 2019, 8(7), 685; https://doi.org/10.3390/cells8070685 - 5 Jul 2019
Cited by 39 | Viewed by 6763
Abstract
Asthma is a common respiratory disease worldwide. Cytokines play a crucial role in the immune system and the inflammatory response to asthma. Abnormal cytokine expression may lead to the development of asthma, which may contribute to pathologies of this disease. As cytokines exhibit [...] Read more.
Asthma is a common respiratory disease worldwide. Cytokines play a crucial role in the immune system and the inflammatory response to asthma. Abnormal cytokine expression may lead to the development of asthma, which may contribute to pathologies of this disease. As cytokines exhibit pleiotropy and redundancy characteristics, we summarized them according to their biologic activity in asthma development. We classified cytokines in three stages as follows: Group 1 cytokines for the epithelial environment stage, Group 2 cytokines for the Th2 polarization stage, and Group 3 cytokines for the tissue damage stage. The recent cytokine-targeting therapy for clinical use (anti-cytokine antibody/anti-cytokine receptor antibody) and traditional medicinal herbs (pure compounds, single herb, or natural formula) have been discussed in this review. Studies of the Group 2 anti-cytokine/anti-cytokine receptor therapies are more prominent than the studies of the other two groups. Anti-cytokine antibodies/anti-cytokine receptor antibodies for clinical use can be applied for patients who did not respond to standard treatments. For traditional medicinal herbs, anti-asthmatic bioactive compounds derived from medicinal herbs can be divided into five classes: alkaloids, flavonoids, glycosides, polyphenols, and terpenoids. However, the exact pathways targeted by these natural compounds need to be clarified. Using relevant knowledge to develop more comprehensive strategies may provide appropriate treatment for patients with asthma in the future. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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12 pages, 576 KiB  
Review
To See or Not to See: A Systematic Review of the Importance of Human Ocular Surface Cytokine Biosignatures in Ocular Allergy
by Esrin Aydin, Moneisha Gokhale, Serap Azizoglu and Cenk Suphioglu
Cells 2019, 8(6), 620; https://doi.org/10.3390/cells8060620 - 20 Jun 2019
Cited by 14 | Viewed by 5134
Abstract
Cytokines are key cell signalling proteins in a number of immune and homeostatic pathways of the human body. In particular, they mediate intracellular mechanisms of allergy on the ocular surface by triggering cellular responses that result in typical physiological ocular allergy symptoms, such [...] Read more.
Cytokines are key cell signalling proteins in a number of immune and homeostatic pathways of the human body. In particular, they mediate intracellular mechanisms of allergy on the ocular surface by triggering cellular responses that result in typical physiological ocular allergy symptoms, such as itchiness, watery eyes, irritation, and swelling. Given the recent research focus in optometry on the aetiology of corneal ectasia subtypes like keratoconus, there is an increasing need for the development of new clinical diagnostic methods. An increasing trend is evident among recent publications in cytokine studies, whereby the concentrations of cytokines in healthy and disease states are compared to derive a specific cytokine profile for that disease referred to as ‘biosignatures’. Biosignatures have diagnostic applications in ocular allergy as a cheap, non-invasive alternative to current techniques like IgE antibody testing and skin prick tests. Cytokine detection from tear samples collected via microcapillary flow can be analysed either by enzyme-linked immunosorbent assays (ELISA), multiplex magnetic bead assays, or immunoblot assays. Characterising patient hypersensitivities through diagnostic tests is the first step to managing exposure to triggers. Investigating cytokine biosignatures in ocular allergy and their links to physiology are imperative and will be the focus of this systematic review article. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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22 pages, 1891 KiB  
Review
Therapeutic Potential of Hematopoietic Prostaglandin D2 Synthase in Allergic Inflammation
by Sonja Rittchen and Akos Heinemann
Cells 2019, 8(6), 619; https://doi.org/10.3390/cells8060619 - 20 Jun 2019
Cited by 55 | Viewed by 8865
Abstract
Worldwide, there is a rise in the prevalence of allergic diseases, and novel efficient therapeutic approaches are still needed to alleviate disease burden. Prostaglandin D2 (PGD2) has emerged as a central inflammatory lipid mediator associated with increased migration, activation and [...] Read more.
Worldwide, there is a rise in the prevalence of allergic diseases, and novel efficient therapeutic approaches are still needed to alleviate disease burden. Prostaglandin D2 (PGD2) has emerged as a central inflammatory lipid mediator associated with increased migration, activation and survival of leukocytes in various allergy-associated disorders. In the periphery, the hematopoietic PGD synthase (hPGDS) acts downstream of the arachidonic acid/COX pathway catalysing the isomerisation of PGH2 to PGD2, which makes it an interesting target to treat allergic inflammation. Although much effort has been put into developing efficient hPGDS inhibitors, no compound has made it to the market yet, which indicates that more light needs to be shed on potential PGD2 sources and targets to determine which particular condition and patient will benefit most and thereby improve therapeutic efficacy. In this review, we want to revisit current knowledge about hPGDS function, expression in allergy-associated cell types and their contribution to PGD2 levels as well as beneficial effects of hPGDS inhibition in allergic asthma, rhinitis, atopic dermatitis, food allergy, gastrointestinal allergic disorders and anaphylaxis. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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24 pages, 3274 KiB  
Review
Mouse Models for Food Allergies: Where Do We Stand?
by Stefan Schülke and Melanie Albrecht
Cells 2019, 8(6), 546; https://doi.org/10.3390/cells8060546 - 6 Jun 2019
Cited by 41 | Viewed by 9254
Abstract
Food allergies are a steadily increasing health and economic problem. Immunologically, food allergic reactions are caused by pathological, allergen-specific Th2 responses resulting in IgE-mediated mast cell degranulation and associated inflammatory reactions. Clinically, food allergies are characterized by local inflammation of the mouth mucosa, [...] Read more.
Food allergies are a steadily increasing health and economic problem. Immunologically, food allergic reactions are caused by pathological, allergen-specific Th2 responses resulting in IgE-mediated mast cell degranulation and associated inflammatory reactions. Clinically, food allergies are characterized by local inflammation of the mouth mucosa, the face, the throat, the gastrointestinal tract, are frequently paralleled by skin reactions, and can result in life-threatening anaphylactic reactions. To better understand food allergies and establish novel treatment options, mouse models are indispensable. This review discusses the available mouse food allergy models, dividing them into four categories: (1) adjuvant-free mouse models, (2) mouse models relying on adjuvants to establish allergen-specific Th2 responses, (3) mouse models using genetically-modified mouse strains to allow for easier sensitization, and (4) humanized mouse models in which different immunodeficient mouse strains are reconstituted with human immune or stem cells to investigate humanized immune responses. While most of the available mouse models can reproducibly portray the immunological parameters of food allergy (Th2 immune responses, IgE production and mast cell activation/expansion), so far, the recreation of the clinical parameters has proven more difficult. Therefore, up to now none of the available mouse models can reproduce the complete human pathology. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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21 pages, 851 KiB  
Review
A Review of Macrophage MicroRNAs’ Role in Human Asthma
by Gavriela Feketea, Corina I Bocsan, Cristian Popescu, Mihaela Gaman, Luminita A Stanciu and Mihnea T Zdrenghea
Cells 2019, 8(5), 420; https://doi.org/10.3390/cells8050420 - 8 May 2019
Cited by 31 | Viewed by 5980
Abstract
There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 [...] Read more.
There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Allergies & Asthma)
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