Sputum <scp>ADAM</scp>8 expression is increased in severe asthma and <scp>COPD</scp>

Oreo, Kevin; Gibson, Peter G.; Simpson, Jodie L.; Wood, Lisa G.; McDonald, Vanessa M.; Baines, Katherine J.

doi:10.1111/cea.12223

Cited by 29 publications

(24 citation statements)

References 49 publications

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“…ADAM8 is induced or upregulated after antigen challenge in mice, or in lung or sputum in human asthma or severe asthma . Further, copy number variation analyses of multiple populations placed ADAM8 in the top three of 61 implicated “asthma genes” .…”

Section: Discussionmentioning

confidence: 99%

“…We now report that eosinophils transition from a morphology similar to that in suspension to a more spread morphology in which the dominant adhesive structures are podosomes containing F-actin, gelsolin and actin-related protein (Arp)-3. In addition, we report that the cells modify the periostin substrate and migrate on periostin in a manner involving disintegrin metalloproteinase-8 (ADAM8), which has been implicated in asthma in several human and mouse studies, [23][24][25][26][27][28][29][30] including in an analysis of copy number variation. 31 2 | ME TH ODS…”

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confidence: 99%

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IL‐5‐stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8‐dependent migration

Johansson

Khanna

Bortnov

et al. 2017

Clin Experimental Allergy

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Summary Background IL-5 causes suspended eosinophils to polarize with filamentous (F)-actin and granules at one pole and the nucleus in a specialized uropod, the “nucleopod”, which is capped with P-selectin glycoprotein ligand-1 (PSGL-1). IL-5 enhances eosinophil adhesion and migration on periostin, an extracellular matrix protein upregulated in asthma by type 2 immunity mediators. Objective Determine how the polarized morphology evolves to foster migration of IL-5-stimulated eosinophils on a surface coated with periostin. Methods Blood eosinophils adhering to adsorbed periostin were imaged at different time points by fluorescent microscopy, and migration of eosinophils on periostin was assayed. Results After 10 min in the presence of IL-5, adherent eosinophils were polarized with PSGL-1 at the nucleopod tip and F-actin distributed diffusely at the opposite end. After 30–60 min, the nucleopod had dissipated such that PSGL-1 was localized in a crescent or ring away from the cell periphery, and F-actin was found in podosome-like structures. The periostin layer, detected with monoclonal antibody Stiny-1, shown here to recognize the FAS1 4 module, was cleared in wide areas around adherent eosinophils. Clearance was attenuated by metalloproteinase inhibitors or antibodies to disintegrin metalloproteinase 8 (ADAM8), a major eosinophil metalloproteinase, previously implicated in asthma pathogenesis. ADAM8 was not found in podosome-like structures, which are associated with proteolytic activity in other cell types. Instead, immunoblotting demonstrated proteoforms of ADAM8 that lack the cytoplasmic tail in the supernatant. Anti-ADAM8 inhibited migration of IL-5-stimulated eosinophils on periostin. Conclusions and Clinical Relevance Migrating IL-5-activated eosinophils on periostin exhibit loss of nucleopodal features and appearance of prominent podosomes along with clearance of the Stiny-1 periostin epitope. Migration and epitope clearance are both attenuated by inhibitors of ADAM8. We propose, therefore, that eosinophils remodel and migrate on periostin-rich extracellular matrix in the asthmatic airway in an ADAM8-dependent manner, making ADAM8 a possible therapeutic target.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

IL‐5‐stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8‐dependent migration

Johansson

Khanna

Bortnov

et al. 2017

Clin Experimental Allergy

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“…Similarly, activin A has been found elevated in patients with asthma and COPD (37, 38) and mice with allergen-induced asthma (37, 39), but its role, although implicated in several mechanisms of inflammation and remodeling, has not been defined fully (39–41). Lastly, LIGHT/LTαβ also strongly induced another proteinase, ADAM-8, that has increasingly been implicated in asthma (42, 43), although this was confined to bronchial-origin epithelial cells and was not seen in the alveolar epithelial cell line. This further promotes the notion that LIGHT or LTαβ may modulate the proteolytic environment and an imbalance between deposition of ECM components and their degradation.…”

Section: Discussionmentioning

confidence: 99%

The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells

Antunes

Madge

Soroosh

et al. 2015

The Journal of Immunology

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Lung epithelial cells are considered important sources of inflammatory molecules and extracellular matrix proteins that contribute to diseases such as asthma. Understanding the factors that stimulate epithelial cells may lead to new insights into controlling lung inflammation. This study sought to investigate the responsiveness of human lung epithelial cells to the TNF family molecules LIGHT and lymphotoxin αβ (LTαβ). Bronchial and alveolar epithelial cell lines, and primary human bronchial epithelial cells, were stimulated with LIGHT and LTαβ, and expression of inflammatory cytokines and chemokines, and markers of epithelial-mesenchymal transition and fibrosis/remodeling, were measured. LTβR, the receptor shared by LIGHT and LTαβ, was constitutively expressed on all epithelial cells. Correspondingly, LIGHT and LTαβ strongly induced a limited but highly distinct set of inflammatory genes in all epithelial cells tested, namely the adhesion molecules ICAM-1 and VCAM-1; the chemokines CCL5, CCL20, CXCL1, CXCL3, CXCL5 and CXCL11; the cytokines IL-6, activin A, and GM-CSF; and metalloproteinases MMP-9 and ADAM-8. Importantly, induction of the majority of these inflammatory molecules was insensitive to the suppressive effects of the corticosteroid budesonide. LIGHT and LTαβ also moderately downregulated E-cadherin, a protein associated with maintaining epithelial integrity, but did not significantly drive production of extracellular matrix proteins or alpha-smooth muscle actin. Thus, LIGHT and LTαβ induce a distinct steroid-resistant inflammatory signature in airway epithelial cells via constitutively expressed LTβR. These findings support our prior murine studies that suggested the receptors for LIGHT and LTαβ contribute to development of lung inflammation characteristic of asthma and idiopathic pulmonary fibrosis.

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“…With the identification of ILC2s as alternative high producers of "type 2" cytokines in asthma, this phenotype may likely be referred to more correctly as "type 2-low" asthma [123]. The role of IgE has not been studied in this asthma phenotype, whereas a role for IL-17 has been reported [124], as well as for IL-33 [125] and ADAM8 [126]. Obesity has been recently identified in population-based studies as a risk factor for both allergy [127] and asthma [4], and obesity-related asthma may represent a distinct nonallergic severe phenotype of asthma [128] associated with a loss of distal lung compliance correlated with weight gain [129].…”

Section: Nonallergic Asthmamentioning

confidence: 99%

Asthma phenotypes and IgE responses

et al. 2015

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The discovery of IgE represented a major breakthrough in allergy and asthma research, whereas the clinical interest given to IgE in asthma has been blurred until the arrival of anti-IgE biotherapy. Novel facets of the complex link between IgE and asthma have been highlighted by the effect of this treatment and by basic research. In parallel, asthma phenotyping recently evolved to the concept of endotypes, relying on identified/suspected pathobiological mechanisms to phenotype patients, but has not yet clearly positioned IgE among biomarkers of asthma.In this review, we first summarise recent knowledge about the regulation of IgE production and its main receptor, FcεRI. In addition to allergens acting as classical IgE inducers, viral infections as well as air pollution may trigger the IgE pathway, notably resetting the threshold of IgE sensitivity by regulating FcεRI expression. We then analyse the place of IgE in different asthma endo/phenotypes and discuss the potential interest of IgE among biomarkers in asthma. @ERSpublications We summarise regulation of IgE production, and discuss IgE in different asthma endo/ phenotypes and among biomarkers

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Sputum ADAM8 expression is increased in severe asthma and COPD

Abstract: ADAM8 expression is increased in both severe asthma and COPD and associated with sputum total cell count and neutrophils. ADAM8 may facilitate neutrophil migration to the airways in severe asthma and COPD.

Cited by 29 publications

References 49 publications

IL‐5‐stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8‐dependent migration

IL‐5‐stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8‐dependent migration

The TNF Family Molecules LIGHT and Lymphotoxin αβ Induce a Distinct Steroid-Resistant Inflammatory Phenotype in Human Lung Epithelial Cells

Asthma phenotypes and IgE responses

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