Airway epithelium–shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling

Altman, Matthew C.; Lü, Ying; Nolin, James D.; Long, Sydney; Chen, Chien‐Chang; Piliponsky, Adrian M.; Altemeier, William A.; Larmore, Megan; Frevert, Charles W.; Mulligan, Michael S.; Ziegler, Steven F.; Debley, Jason S.; Peters, Michael C.; Hallstrand, Teal S.

doi:10.1172/jci126402

Cited by 63 publications

(71 citation statements)

References 79 publications

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“…[14][15][16] Moreover, IL33 may have a paracrine effect on the airway epithelium, as this epithelium has been shown to be responsive to IL33. 17,18 These data suggest a connection among epithelium-derived IL33, eosinophilic inflammation, and asthma.…”

mentioning

confidence: 78%

Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar

Portelli

Dijk

et al. 2021

Journal of Allergy and Clinical Immunology

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Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV 1 , FEV 1 / forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma. (J Allergy Clin Immunol 2020;nnn:nnn-nnn.)

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confidence: 78%

Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar

Portelli

Dijk

et al. 2021

Journal of Allergy and Clinical Immunology

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“…We also examined the expression of ACE2 and TMPRSS2 in ex vivo cultured lower airway epithelial cells (AECs) from children with and without asthma both at baseline and during infection with HRV-A16 for 48 hours (6). There were no significant differences in the age, sex, baseline FEV 1 , and fraction of exhaled nitric oxide (FeNO) between the groups, but the children with asthma had more airflow obstruction measured by the FEV 1 /FVC ratio (P = 0.02), significantly higher total serum immunoglobulin E levels (mean values of 381 versus 16 kU/L, P = 0.01) and higher number of positive allergen-specific IgE titers on radioallergosorbent (RAST) testing (mean values of 2.7 versus 0, P <0.01) relative to healthy control children.…”

Section: To the Editormentioning

confidence: 99%

Effects of Asthma and Human Rhinovirus A16 on the Expression of SARS-CoV-2 Entry Factors in Human Airway Epithelium

Murphy

Lü

Barrow³

et al. 2020

Am J Respir Cell Mol Biol

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“…A recent study shows that asthmatic Type 2 inflammation and airway hyperresponsiveness are related to mast cell infiltration into the airway epithelium and that AECs and mast cells communicate through IL-33 signaling that regulates inflammation (Altman et al, 2019). In allergic asthma, the inflammatory process is initiated by Th2 cells that produce cytokines, such as IL-4, IL-5, IL-9, IL-13, leading to the production of IgE, eosinophilia, and goblet cell hyperplasia (Whitsett and Alenghat, 2015;Athari, 2019).…”

Section: Epithelial Functions In Asthmamentioning

confidence: 99%

Airway Epithelial Dynamics in Allergy and Related Chronic Inflammatory Airway Diseases

Laulajainen‐Hongisto

Toppila‐Salmi

Luukkainen

et al. 2020

Front. Cell Dev. Biol.

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Allergic rhinitis, chronic rhinosinusitis, and asthma are highly prevalent, multifactorial chronic airway diseases. Several environmental and genetic factors affect airway epithelial dynamics leading to activation of inflammatory mechanisms in the airways. This review links environmental factors to host epithelial immunity in airway diseases. Understanding altered homeostasis of the airway epithelium might provide important targets for diagnostics and therapy of chronic airway diseases.

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Airway epithelium–shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signaling

Cited by 63 publications

References 79 publications

Phenotypic and functional translation of IL33 genetics in asthma

Phenotypic and functional translation of IL33 genetics in asthma

Effects of Asthma and Human Rhinovirus A16 on the Expression of SARS-CoV-2 Entry Factors in Human Airway Epithelium

Airway Epithelial Dynamics in Allergy and Related Chronic Inflammatory Airway Diseases

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