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| Open AccessCullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity
Asthma may be exacerbated by respiratory viral infection, but the cellular and molecular mechanisms are still unclear. Here the authors show, using mouse models of asthma with influenza infection, that asthma-induced cullin5 in alveolar macrophages suppresses IFN-β production to promote neutrophilic inflammation but dampens antiviral immunity.
- Haibo Zhang
- , Keke Xue
- & Lei Sun
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Article
| Open AccessEpithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling
IL-17 mediated inflammation in the lung is mediated by different effector molecules. Here the authors show that the epigenetic regulator epithelial sirtuin 6 (Sirt6) is associated with lung inflammation in asthma patients and that Sirt6 contributes to promotion of inflammation in mouse asthma models.
- Jingyun Quan
- , Xiaoxia Wen
- & Tianwen Lai
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Article
| Open AccessRNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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Article
| Open AccessThe airway microbiota of neonates colonized with asthma-associated pathogenic bacteria
Here, Thorsen et al. bridge new and previous results from the COPSAC2000 prospective birth cohort and the later COPSAC2010 cohort, by constructing a combined bacterial pathogen score with implications for the early-life airway microbiota and the risk of asthma later in childhood
- Jonathan Thorsen
- , Xuan Ji Li
- & Jakob Stokholm
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Article
| Open AccessOrai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
The regulation and intracellular transport of Ca2+ in immune cells involves Ca2+ release-activated Ca2+ (CRAC) channels. Here the authors show targeting CRAC components Orai1 and Orai2 modulates pulmonary ILC2 cells altering their metabolism, function and is linked to alleviation of immunopathology in a murine model of allergic airway disease.
- Emily Howard
- , Benjamin P. Hurrell
- & Omid Akbari
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Article
| Open AccessDelayed gut microbiota maturation in the first year of life is a hallmark of pediatric allergic disease
Here, using participants in the CHILD birth cohort, the authors reveal that impaired 1-year microbiota maturation may be universal to 5-year pediatric allergies, mediated by functional and metabolic imbalances of compromised mucous integrity, elevated oxidative activity, decreased fermentation, and elevated trace amines.
- Courtney Hoskinson
- , Darlene L. Y. Dai
- & Stuart E. Turvey
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Article
| Open AccessType-2 CD8+ T-cell formation relies on interleukin-33 and is linked to asthma exacerbations
The most appreciated producers of pathogenic type-2 cytokines in asthma are T helper 2 cells and group 2 innate lymphoid cells, however, CD8+ cytotoxic T cells are also capable of secreting these mediators. Authors here show that IL-33, a cytokine that is produced by the inflammatory microenvironment, promotes type-2 cytotoxic T cell development, which is linked to asthma exacerbations.
- Esmee K. van der Ploeg
- , Lisette Krabbendam
- & Ralph Stadhouders
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Article
| Open AccessSUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
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Article
| Open AccessRhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19
Viral infections and exposure to inhaled allergens are linked to asthma onset, exacerbations and progression. Here, the authors used controlled experimental rhinovirus infection in patients with and without asthma, and further assessed in vitro the role of house dust mite allergen combined with rhinovirus and SARS-CoV-2 infection. They discovered that rhinovirus-induced activation of epithelial RIG-I inflammasome supresses antiviral immunity, promotes inflammation during asthma exacerbations and aggravates subsequent infection with SARS-CoV-2, particularly upon house dust mite exposure.
- Urszula Radzikowska
- , Andrzej Eljaszewicz
- & Milena Sokolowska
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Article
| Open AccessLung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.
- Youn Jung Choi
- , Ji-Seung Yoo
- & Jae U. Jung
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Article
| Open AccessNasal DNA methylation at three CpG sites predicts childhood allergic disease
Accurate prediction of the onset of childhood allergy is important to clarify the difference between various respiratory diseases. Here the authors propose that the methylation status of three sites in nasal DNA predicts the onset of childhood allergy which may aid diagnosis and monitoring.
- Merlijn van Breugel
- , Cancan Qi
- & Cheng-Jian Xu
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Article
| Open AccessThe endocannabinoid anandamide is an airway relaxant in health and disease
Obstructive lung diseases are a frequent cause of morbidity worldwide. Here, the authors identify the endocannabinoid anandamide (AEA) as an airway relaxant under physiological and pathophysiological conditions that can be locally applied to the lung as an aerosol in mice.
- Annika Simon
- , Thomas von Einem
- & Daniela Wenzel
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Article
| Open AccessDiscerning asthma endotypes through comorbidity mapping
Asthma is a heterogeneous, complex syndrome that arises in individuals with various genetic and exposure variations. Here, the authors show that disease comorbidity patterns can serve as a surrogate for these variations, and identify asthma endotypes distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes.
- Gengjie Jia
- , Xue Zhong
- & Julian Solway
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Article
| Open AccessContext-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march
Allergic sensitisation in the skin can lead to allergic dermatitis and further to airway asthma in a process of atopic march. Here the authors examine the difference between superficial or deep skin sensitisation, characterise the immune cells generated and show differential TSLP and IL-1β involvement.
- Justine Segaud
- , Wenjin Yao
- & Mei Li
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Article
| Open AccessPD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability
Regulatory T (Treg) cells have been implicated in the induction of airway tolerance and amelioration of respiratory duct inflammation. Here the authors show, using PD-L2 deficient mice, that the immune suppression signal from PD-L2 is important for modulating Treg cell metabolism and function for proper induction of respiratory tolerance in mice.
- Benjamin P. Hurrell
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessRNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R
The function of RNA binding proteins within innate lymphoid cells (ILC) has been partially characterised. Here the authors show that RBM3 functions to limit the type 2 immunity promoting activity of ILC2 partially through cysteinyl leukotriene 1 receptor.
- Jana H. Badrani
- , Allyssa N. Strohm
- & Taylor A. Doherty
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Article
| Open AccessCigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells
Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
- Jongho Ham
- , Jihyun Kim
- & Hye Young Kim
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Article
| Open AccessNasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
- Satria P. Sajuthi
- , Jamie L. Everman
- & Max A. Seibold
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Article
| Open AccessDual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice
Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.
- Eva Conde
- , Romain Bertrand
- & Laurent L. Reber
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Article
| Open AccessCD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma
The role of the CD200–CD200R axis in regulating pulmonary inflammation is not completely understood. Here the authors show CD200R is expressed on type 2 innate lymphoid cells (ILC2s), and its engagement by CD200 ameliorates airway hyperreactivity and allergic asthma via inhibition of NF-κB signaling.
- Pedram Shafiei-Jahani
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessDisulfide disruption reverses mucus dysfunction in allergic airway disease
In asthma, mucus plugging is an important cause of airflow obstruction, but it is not targeted by widely used bronchodilator and anti-inflammatory drugs. Here the authors show that reduction of disulfide bonds that hold mucin polymers together reverses asthma-like obstruction in mice.
- Leslie E. Morgan
- , Ana M. Jaramillo
- & Christopher M. Evans
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Article
| Open AccessGenome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity.
- Yi Han
- , Qiong Jia
- & Hooman Allayee
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Article
| Open AccessDiscovering the genes mediating the interactions between chronic respiratory diseases in the human interactome
Complex diseases often share genetic determinants and symptoms, but the mechanistic basis of disease interactions remains elusive. Here, the authors propose a network topological measure to identify proteins linking complex diseases in the interactome, and identify mediators between COPD and asthma.
- Enrico Maiorino
- , Seung Han Baek
- & Amitabh Sharma
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Article
| Open AccessPrenatal dietary supplements influence the infant airway microbiota in a randomized factorial clinical trial
Here, the authors present the results of a mother–child cohort randomized clinical trial of n-3 LCPUFA and vitamin D maternal supplementation, finding an association between supplement-induced microbiota changes in infant airways at age 1-month but not the infant fecal or maternal vaginal microbiome.
- Mathis H. Hjelmsø
- , Shiraz A. Shah
- & Hans Bisgaard
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Article
| Open AccessEighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.
- Thorunn A. Olafsdottir
- , Fannar Theodors
- & Kari Stefansson
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Article
| Open AccessInfant airway microbiota and topical immune perturbations in the origins of childhood asthma
Here, Thorsen et al. examine the microbiota during the first three months of life in a cohort of 700 children and find that microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at one month of age are associated with topical immune mediators and asthma by age 6 years.
- Jonathan Thorsen
- , Morten A. Rasmussen
- & Hans Bisgaard
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Article
| Open AccessDouble negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma
Allergic asthma symptoms may be controlled, but currently no effective therapy exist to address the underlying pathology. Here the authors show, using mouse model of adoptive cell transfer, that CD4-CD8- T cells can suppress the function of dendritic cells and T follicular helper cells via Lag3 to provide allergen-specific protection from asthma.
- Dan Tian
- , Lu Yang
- & Dong Zhang
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Article
| Open AccessThe nasal methylome as a biomarker of asthma and airway inflammation in children
Epigenetic differences in nasal epithelium have been proposed as a biomarker for lower airway disease and asthma. Here, in epigenome-wide association studies for asthma and other airway traits using nasal swabs, the authors identify differentially methylated CpGs that highlight genes involved in TH2 response.
- Andres Cardenas
- , Joanne E. Sordillo
- & Diane R. Gold
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Article
| Open AccessAssociation study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations
The burden of asthma varies between ancestries, but GWAS have so far focused on mainly European ancestry populations. Here, Daya et al. perform GWAS for asthma in 14,654 individuals of African ancestry and, besides confirming previously known loci, identify two potentially African ancestry-specific loci.
- Michelle Daya
- , Nicholas Rafaels
- & Maria Yazdanbakhsh
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Article
| Open AccessPreventing acute asthmatic symptoms by targeting a neuronal mechanism involving carotid body lysophosphatidic acid receptors
Acute bronchoconstriction is the leading cause of asthmatic sudden death following allergen exposure. The authors show that the systemic increase of LPA following inhaled allergen or bradykinin challenge activates the carotid bodies through TRPV1 and LPA-specific receptors and that systemic TRPV1 and LPA-specific receptor antagonists ameliorate acute bronchoconstriction.
- Nicholas G. Jendzjowsky
- , Arijit Roy
- & Richard J. A. Wilson
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Article
| Open AccessDelayed gut microbiota development in high-risk for asthma infants is temporarily modifiable by Lactobacillus supplementation
Gut microbial dysbiosis in infancy is associated with childhood atopy and the development of asthma. Here, the authors show that gut microbiota perturbation is evident in the very earliest stages of postnatal life, continues throughout infancy, and can be partially rescued by Lactobacillus supplementation in high-risk for asthma infants.
- Juliana Durack
- , Nikole E. Kimes
- & Susan V. Lynch
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Article
| Open AccessNicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity
Airway hyperreactivity is driven by type 2 cytokines produced by ILC2 and Th2 cells. Here the authors show that an α7-nicotinic receptor agonist (GTS-21) inhibits ILC2 responses and is therapeutic against Alternaria-induced airway hyperreactivity in a humanized mouse model.
- Lauriane Galle-Treger
- , Yuzo Suzuki
- & Omid Akbari
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Article
| Open Access1,25D3 prevents CD8+Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter
Type 2 CD8+ T cells (Tc2) play a role in the development of experimental asthma. Here the authors show that 1,25D3, the active form of vitamin D3, can prevent conversion of CD8+T cells to a Tc2 phenotype, reducing asthma susceptibility.
- Michaela Schedel
- , Yi Jia
- & Erwin W. Gelfand
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Article
| Open AccessMeta-analysis identifies seven susceptibility loci involved in the atopic march
The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.
- Ingo Marenholz
- , Jorge Esparza-Gordillo
- & Young Ae Lee
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Article
| Open AccessOxidation of the alarmin IL-33 regulates ST2-dependent inflammation
IL-33, released by epithelial cells in response to stress, is a potent activator of inflammation. Here Cohenet al. show that secreted IL-33 is rapidly inactivated by disulfide bond formation that prevents binding to its receptor, and that IL-33-related cytokines are susceptible to similar oxidation.
- E. Suzanne Cohen
- , Ian C. Scott
- & Tomas Mustelin
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Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation
Syndecan-4 is a surface protein implicated in the regulation of cytoskeleton, adhesion and migration. Here the authors show that blocking syndecan-4 prevents dendritic cell migration into the lung and inhibits the development of allergic airway inflammation in mice.
- Tobias Polte
- , Susanne Petzold
- & Marco Averbeck
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Article |
Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites
Growing evidence suggests that environmental rather than genetic factors are major contributors to asthma development. Here the authors show that high intake of dietary fibre by pregnant mice increases resistance of their progeny to the development of allergic airways disease.
- Alison N. Thorburn
- , Craig I. McKenzie
- & Charles R. Mackay
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Article |
A fungal protease allergen provokes airway hyper-responsiveness in asthma
Airway hyper-responsiveness, a hallmark of asthma, is often associated with sensitization to fungi. Here, the authors show that a fungal protease allergen Asp f13/Alp1 from Aspergillus fumigatuscan promote airway hyper-responsiveness in asthma via its effect on the airway smooth muscle cells.
- Nariman A. Balenga
- , Michael Klichinsky
- & Kirk M. Druey
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Article |
Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase
House dust mites are a common cause of allergic asthma. Here, the authors show that the Th2-mediated inflammatory responses triggered by mites in mouse airways are mediated by the activation of DNA-dependent protein kinase (DNA-PK) in dendritic cells.
- Amarjit Mishra
- , Alexandra L. Brown
- & Jay H. Chung
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Article |
The polymeric mucin Muc5ac is required for allergic airway hyperreactivity
Asthma is associated with mucus overproduction; however, the immunological consequences of excess mucus remain poorly understood. Here the authors show that formation of airway plugs by mucus promotes airway hypersensitivity, while deletion of mucous component Muc5acablates it independently of inflammation.
- Christopher M. Evans
- , Dorota S. Raclawska
- & Burton F. Dickey
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Article
| Open AccessEthnic-specific associations of rare and low-frequency DNA sequence variants with asthma
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
- Catherine Igartua
- , Rachel A. Myers
- & Carole Ober
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Article |
Grail controls Th2 cell development by targeting STAT6 for degradation
The mechanisms controlling Th2-mediated inflammation are not well defined. Here the authors show that the E3 ubiquitin ligase Grail is involved in a negative feedback loop with Th2-specific transcription factors and regulates Th2-mediated allergic asthma responses.
- Anupama Sahoo
- , Andrei Alekseev
- & Roza Nurieva
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Article |
Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation
Allergic airway inflammation in asthma can be treated with corticosteroids, but some patients remain unresponsive to this therapy. Here, Kabata et al. show that thymic stromal lymphopoietin contributes to the corticosteroid resistance during airway inflammation through its action on natural helper cells.
- Hiroki Kabata
- , Kazuyo Moro
- & Koichiro Asano
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Article |
ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48
ORMDL3has been identified as a gene associated with asthma susceptibility, but its exact role in the pathogenesis of this disease is not well known. Here, the authors propose that induction of ORMDL3 in eosinophils modulates the expression of integrins, which could contribute to a key inflammatory event in asthma.
- Sung Gil Ha
- , Xiao Na Ge
- & P. Sriramarao
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Article |
Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation
Inositol polyphosphate 4 phosphatase regulates phosphoinositide signalling and is associated with an increased risk of asthma. Aichet al. show that, in a mouse model of airway inflammation, calpains degrade inositol polyphosphate 4 phosphatase resulting in exacerbated phosphoinositide 3-kinase signalling.
- Jyotirmoi Aich
- , Ulaganathan Mabalirajan
- & Balaram Ghosh