In past 10 years, microRNAs (miRNAs) have gained scientific attention due to their importance in the pathophysiology of allergic diseases and their potential as biomarkers in liquid biopsies. They ...act as master post‐transcriptional regulators that control most cellular processes. As one miRNA can target several mRNAs, often within the same pathway, dysregulated expression of miRNAs may alter particular cellular responses and contribute, or lead, to the development of various diseases. In this review, we give an overview of the current research on miRNAs in allergic diseases, including atopic dermatitis, allergic rhinitis, and asthma. Specifically, we discuss how individual miRNAs function in the regulation of immune responses in epithelial cells and specialized immune cells in response to different environmental factors and respiratory viruses. In addition, we review insights obtained from experiments with murine models of allergic airway and skin inflammation and offer an overview of studies focusing on miRNA discovery using profiling techniques and bioinformatic modeling of the network effect of multiple miRNAs. In conclusion, we highlight the importance of research into miRNA function in allergy and asthma to improve our knowledge of the molecular mechanisms involved in the pathogenesis of this heterogeneous group of diseases.
Background
miRNAs are master regulators of signaling pathways critically involved in asthma and are transferred between cells in extracellular vesicles (EV). We aimed to investigate whether the miRNA ...content of EV secreted by primary normal human bronchial epithelial cells (NHBE) is altered upon asthma development.
Methods
NHBE cells were cultured at air‐liquid interface and treated with interleukin (IL)‐13 to induce an asthma‐like phenotype. EV isolations by precipitation from basal culture medium or apical surface wash were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blot, and EV‐associated miRNAs were identified by a RT‐qPCR‐based profiling. Significant candidates were confirmed in EVs isolated by size‐exclusion chromatography from nasal lavages of children with mild‐to‐moderate (n = 8) or severe asthma (n = 9), and healthy controls (n = 9).
Results
NHBE cells secrete EVs to the apical and basal side. 47 miRNAs were expressed in EVs and 16 thereof were significantly altered in basal EV upon IL‐13 treatment. Expression of miRNAs could be confirmed in EVs from human nasal lavages. Of note, levels of miR‐92b, miR‐210, and miR‐34a significantly correlated with lung function parameters in children (FEV1FVC%pred and FEF25‐75%pred), thus lower sEV‐miRNA levels in nasal lavages associated with airway obstruction. Subsequent ingenuity pathway analysis predicted the miRNAs to regulate Th2 polarization and dendritic cell maturation.
Conclusion
Our data indicate that secretion of miRNAs in EVs from the airway epithelium, in particular miR‐34a, miR‐92b, and miR‐210, might be involved in the early development of a Th2 response in the airways and asthma.
Primary human bronchial epithelial cells secrete microRNA‐containing extracellular vesicles (EV) apically and basally. Upon Interleukin‐13‐induced goblet cell metaplasia, miR‐34a, miR‐92b, and miR‐210 levels in EVs are lower, which is predicted to influence dendritic cell maturation and Th2 polarization. Lower levels of these microRNAs in EVs in nasal lavages correlate with increased airway obstruction in children.
Emerging research suggests that exposures occurring years before conception are important determinants of the health of future offspring and subsequent generations. Environmental exposures of both ...the father and mother, or exposure to disease processes such as obesity or infections, may influence germline cells and thereby cause a cascade of health outcomes in multiple subsequent generations. There is now increasing evidence that respiratory health is influenced by parental exposures that occur long before conception. The strongest evidence relates adolescent tobacco smoking and overweight in future fathers to increased asthma and lower lung function in their offspring, supported by evidence on parental preconception occupational exposures and air pollution. Although this literature is still sparse, the epidemiological analyses reveal strong effects that are consistent across studies with different designs and methodologies. The results are strengthened by mechanistic research from animal models and (scarce) human studies that have identified molecular mechanisms that can explain the epidemiological findings, suggesting transfer of epigenetic signals through germline cells, with susceptibility windows in utero (both male and female line) and prepuberty (male line).
The concept that our lifestyles and behaviours may influence the health of our future children represents a new paradigm. This raises concerns for future health in decades to come with respect to harmful exposures but may also open for radical rethinking of preventive strategies that may improve health in multiple generations, reverse the imprint of our parents and forefathers, and underpin strategies that can break the vicious circle of propagation of health inequalities across generations.
Background Chronic immune diseases, such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms but cannot cure the disease. This prompted demands for alternatives to ...pharmaceuticals, such as probiotics, for the prevention of allergic disease. However, clinical trials have produced inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host's microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. Objective We sought to identify and characterize a bioactive probiotic metabolite for potential prevention of allergic airway disease. Methods Probiotic supernatants were screened for their ability to concordantly decrease the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. Results Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of 2 supernatants according to polarity, followed by total ion chromatography and mass spectrometry, yielded C11 H12 N2 O2 as the molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-tryptophan. In contrast, L-tryptophan and 11 other D-amino acids were inactive. Feeding D-tryptophan to mice before experimental asthma induction increased numbers of lung and gut regulatory T cells, decreased lung TH 2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced gut microbial diversity, which was increased by D-tryptophan. Conclusions D-tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products can be exploited in novel preventative strategies for chronic immune diseases.
miRNAs in Lung Development and Diseases Boateng, Eistine; Krauss-Etschmann, Susanne
International journal of molecular sciences,
04/2020, Letnik:
21, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The development of the lung involves a diverse group of molecules that regulate cellular processes, organ formation, and maturation. The various stages of lung development are marked by accumulation ...of small RNAs that promote or repress underlying mechanisms, depending on the physiological environment
and postnatally. To some extent, the pathogenesis of various lung diseases is regulated by small RNAs. In this review, we discussed miRNAs regulation of lung development and diseases, that is, COPD, asthma, pulmonary fibrosis, and pulmonary arterial hypertension, and also highlighted possible connotations for human lung health.
Summary
Background
The prevalence of asthma and chronic obstructive pulmonary disease (COPD) has risen markedly over the last decades and is reaching epidemic proportions. However, underlying ...molecular mechanisms are not fully understood, hampering the urgently needed development of approaches to prevent these diseases. It is well established from epidemiological studies that prenatal exposure to cigarette smoke is one of the main risk factors for aberrant lung function development or reduced fetal growth, but also for the development of asthma and possibly COPD later in life. Of note, recent evidence suggests that the disease risk can be transferred across generations, that is, from grandparents to their grandchildren. While initial studies in mouse models on in utero smoke exposure have provided important mechanistic insights, there are still knowledge gaps that need to be filled.
Objective
Thus, in this review, we summarize current knowledge on this topic derived from mouse models, while also introducing two other relevant animal models: the fruit fly Drosophila melanogaster and the zebrafish Danio rerio.
Methods
This review is based on an intensive review of PubMed‐listed transgenerational animal studies from 1902 to 2018 and focuses in detail on selected literature due to space limitations.
Results
This review gives a comprehensive overview of mechanistic insights obtained in studies with the three species, while highlighting the remaining knowledge gaps. We will further discuss potential (dis)advantages of all three animal models.
Conclusion/Clinical Relevance
Many studies have already addressed transgenerational inheritance of disease risk in mouse, zebrafish or fly models. We here propose a novel strategy for how these three model organisms can be synergistically combined to achieve a more detailed understanding of in utero cigarette smoke‐induced transgenerational inheritance of disease risk.
Background
Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs ...remain elusive. In this study, we investigated epigenetic miR‐associated mechanisms in the sputum of grass pollen‐allergic patients with and without allergen‐specific immunotherapy (AIT).
Methods
Induced sputum samples of healthy controls (HC), AIT‐treated and ‐untreated grass pollen‐allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and whole‐transcriptome microarray analysis of the same samples. miR targets were predicted in silico and used to identify inverse regulation. Local PGE2 levels were measured using ELISA.
Results
Two hundred and fifty nine miRs were upregulated in the sputum of AA patients compared with HC, while only one was downregulated. The inverse picture was observed in induced sputum of AIT‐treated patients: while 21 miRs were downregulated, only 4 miRs were upregulated in asthmatics upon AIT. Of these 4 miRs, miR‐3935 stood out, as its predicted target PTGER3, the prostaglandin EP3 receptor, was downregulated in treated AA patients compared with untreated. The levels of its ligand PGE2 in the sputum supernatants of these samples were increased in allergic patients, especially asthmatics, and downregulated after AIT. Finally, local PGE2 levels correlated with ILC2 frequencies, secreted sputum IL‐13 levels, inflammatory cell load, sputum eosinophils and symptom burden.
Conclusions
While profiling the sputum of allergic patients for novel miR expression patterns, we uncovered an association between miR‐3935 and its predicted target gene, the prostaglandin E3 receptor, which might mediate AIT effects through suppression of the PGE2‐PTGER3 axis.
miR‐3935 is upregulated in sputum cells of allergic asthma patients, who received allergen‐specific immunotherapy treatement, while mRNA levels of its predicted target, the prostaglandin E2 receptor, is downregulated as its ligand PGE2 as well. PGE2 is strongly upregulated in sputum supernatants of untreated allergic patients and is reduced in patients, who received allergen‐specific immunotherapy. PGE2 levels correlate with clinical parameters, like eosinophils and symptom score.
In order to summarize recent research on the prevention of allergies-particularly asthma-and stimulate new activities for future initiatives, a virtual workshop sponsored by the EAACI Clemens von ...Pirquet foundation and EUFOREA was held in October 2021. The determinants of the "allergic march" as well as the key messages from intervention studies were reviewed by an international faculty of experts. Several unmet needs were identified, and a number of priorities for future studies were proposed.
Summary
T‐helper cell type 17 (Th17) mediated inflammation is associated with various diseases including autoimmune encephalitis, inflammatory bowel disease and lung diseases such as chronic ...obstructive pulmonary disease and asthma. Differentiation into distinct T helper subtypes needs to be tightly regulated to ensure an immunological balance. As microRNAs (miRNAs) are critical regulators of signalling pathways, we aimed to identify specific miRNAs implicated in controlling Th17 differentiation. We were able to create a regulatory network model of murine T helper cell differentiation by combining Affymetrix mRNA and miRNA arrays and in silico analysis. In this model, the miR‐212~132 and miR‐182~183 clusters were significantly up‐regulated upon Th17 differentiation, whereas the entire miR‐106~363 cluster was down‐regulated and predicted to target well‐known Th17 cell differentiation pathways. In vitro transfection of miR‐18b, miR‐106a and miR‐363‐3p into primary murine Cd4+ lymphocytes decreased expression of retinoid‐related orphan receptor c (Rorc), Rora, Il17a and Il17f, and abolished secretion of Th17‐mediated interleukin‐17a (Il17a). Moreover, we demonstrated target site‐specific regulation of the Th17 transcription factors Rora and nuclear factor of activated T cells (Nfat) 5 by miR‐18b, miR‐106a and miR‐363‐3p through luciferase reporter assays. Here, we provide evidence that miRNAs are involved in controlling the differentiation and function of T helper cells, offering useful tools to study and modify Th17‐mediated inflammation.
By combining mRNA and miRNA microarray analysis of in vitro differentiated T helper type 2 (Th2) and Th17 cells, we generated an in silico regulatory network model or Th cell differentiation. Further, we identified miR‐18b, miR‐106a and miR‐363‐3p to specifically target Th17 transcription factors Rora, Nfat5 and Rorc and thus to be involved in Th17 differentiation and function. Here, we provide evidence that miRNAs are involved in controlling the differentiation and function of T helper cells, offering useful tools to study and modify Th17‐mediated inflammation.
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