IL-17RA Signaling in Airway Inflammation and Bronchial Hyperreactivity in Allergic Asthma

Willis, Cynthia R.; Siegel, Lori; Leith, Anh; Mohn, Deanna; Escobar, Sabine; Wannberg, Sharon; Misura, Kira; Rickel, Erika; Rottman, James B.; Comeau, Michael R.; Sullivan, John K.; Metz, Daniela; Tocker, Joel; Budelsky, Alison

doi:10.1165/rcmb.2015-0038oc

Cited by 58 publications

(51 citation statements)

References 48 publications

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“…The Amgen cDNA libraries were prepared from total RNA isolated using Mirvana miRNA isolation kits (Ambion, Grand Island, NY) with on-colum DNase treatment as described previously60. Total RNA quality and concentration was determined using Bioanalzyer (Agilent, Santa Clara, CA) and NanoDrop (ThermoScientific, Wilmington, DE) instruments.…”

Section: Methodsmentioning

confidence: 99%

Defining an olfactory receptor function in airway smooth muscle cells

Aisenberg

Huang

Zhu

et al. 2016

Sci Rep

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Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (Golf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.

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Section: Methodsmentioning

confidence: 99%

Defining an olfactory receptor function in airway smooth muscle cells

Aisenberg

Huang

Zhu

et al. 2016

Sci Rep

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“…[5][6][7] Increased levels of IL-17 in bronchoalveolar lavage fluid (BALF), blood and sputum of patients with allergic asthma have been reported. 8 Sequencing studies revealed that IL-17 activates stromal cells to release chemokines and cytokines and increases the expression of extracellular matrix proteins in allergic asthma. 9,10 In addition, IL-17 enhances eosinophilic recruitment during airway inflammation in allergic asthma.…”

Section: Introductionmentioning

confidence: 99%

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

et al. 2018

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Interleukin (IL)-17 is a major contributor to the pathogenesis of allergic asthma. Developmental endothelial locus-1 (Del-1) is an endothelial cell-secreted protein known to inhibit IL-17 expression. However, little is known about the association between Del-1 and IL-17 in the pathogenesis of allergic asthma. Using bronchoalveolar lavage fluid (BALF) and peripheral blood samples collected from allergic asthmatic patients and controls, we explored the role of Del-1 in relation to IL-17 in allergic asthma. We found that the negative correlation between Del-1 and IL-17 was significant in BALF of allergic asthmatics. Del-1 treatment inhibited the expression of IL-17, the differentiation of IL-17-secreting leukocytes and associated cytokines. Contrarily, IL-17 levels were increased after treatment with anti-Del-1 mAb. Consistent with this, Del-1 treatment led to downregulation of IL-5, CCL5 and IL-4, thus reducing secretion of eosinophil cationic protein. Furthermore, Del-1 significantly downregulated the expression of ICAM-1 and may have the potential to reduce leukocyte transendothelial migration. Our data demonstrate that Del-1 can negatively regulate IL-17 and its proinflammatory function, thereby limiting airway inflammation in allergic asthmatics, and suggest Del-1 as a potential candidate for prevention and treatment of allergic asthma.

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“…Moreover, IL-17A may also be involved in airway remodeling. IL-17A has been reported to increase airway smooth muscle contraction on methacholine stimulation and drive migration of airway smooth muscle cells in murine models of allergic inflammation and in patients with asthma 9, 14, 15. IL-17A binds to the receptor subunits IL-17RA and C, which are expressed on epithelial and mesenchymal cells as well as on some immune cell populations such as lymphocytes, dendritic cells, and monocytes/macrophages in the lung 16 .…”

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confidence: 99%

“…Mice that lack IL-17RA produce less CXCL1 and CXCL2 on pulmonary challenge with Klebsiella pneumoniae 17 and IL-17RA signaling is also necessary for host defense against Candida albicans 18 . In 2 mouse models, blocking IL-17R and IL-17RB reduced airway inflammation and airway hyperreactivity 14 . T H 17 cells also secrete IL-22, and IL-22 mRNA is elevated in PBMCs in pediatric patients with severe asthma, and rhinitis 19 .…”

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confidence: 99%

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

Andersson

Adams

Nagakumar

et al. 2017

Journal of Allergy and Clinical Immunology

105

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BackgroundNeutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in pediatric asthma is unknown.ObjectivesWe sought to investigate the role of neutrophils and the IL-17A pathway in mediating pediatric severe therapy-resistant asthma (STRA).MethodsChildren with STRA (n = 51; age, 12.6 years; range, 6-16.3 years) and controls without asthma (n = 15; age, 4.75 years; range, 1.6-16 years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings, and biopsy. Neutrophils, IL-17A, and IL-17RA–expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells were stimulated with IL-17A and/or IL-22, with and without budesonide.ResultsChildren with STRA had increased intraepithelial neutrophils, which positively correlated with FEV1 %predicted (r = 0.43; P = .008). Neutrophilhigh patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in children with STRA. Submucosal and epithelial IL-17A–positive cells and BAL IL-17A and IL-22 levels were similar in children with STRA and controls. However, there were significantly more IL-17RA–positive cells in the submucosa and epithelium in children with STRA compared with controls (P = .001). Stimulation of primary bronchial epithelial cells with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of budesonide.ConclusionsA proportion of children with STRA exhibit increased intraepithelial airway neutrophilia that correlated with better lung function. STRA was also characterized by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in pediatric severe asthma pathophysiology.

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IL-17RA Signaling in Airway Inflammation and Bronchial Hyperreactivity in Allergic Asthma

Cited by 58 publications

References 48 publications

Defining an olfactory receptor function in airway smooth muscle cells

Defining an olfactory receptor function in airway smooth muscle cells

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

Intraepithelial neutrophils in pediatric severe asthma are associated with better lung function

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