Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Abstract

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.

Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA

“…To explore the biological role of ADAM33 / Adam33 in asthma progression, we have developed a series of mouse models 7 . We therefore set out to identify analogs of the human lead ASOs that could silence mouse Adam33 expression.…”

“…Single-nucleotide polymorphisms in ADAM33 have been linked to asthma and bronchial hyperresponsiveness 4, 56, 7. Furthermore, in human embryonic lung explant culture, treatment with sADAM33 induces angiogenesis 8 and myogenesis, 7 pathological features of airway remodeling in asthma.…”

“…Furthermore, in human embryonic lung explant culture, treatment with sADAM33 induces angiogenesis 8 and myogenesis, 7 pathological features of airway remodeling in asthma. Expression of human sADAM33 in transgenic mice causes pathological airway remodeling and makes airways more susceptible to allergen-induced inflammatory responses 7 . Promisingly, when induction of human sADAM33 is arrested, this leads to reversal of the remodeling and reduced sensitivity to inflammatory responses 7 .…”

IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type‐2 inflammatory endotype

“…ADAM33 belongs to a disintegrin and zinc‐dependent metalloprotease family and exhibits a complex organization that includes eight domains: signal sequence, prodomain, catalytic, disintegrin, cysteine rich, epidermal growth factor like, transmembrane, and cytoplasmic. A recent study revealed that in Adam33 ‐null mice, airway remodelling and inflammation after allergen challenge were both suppressed, suggesting an essential role of ADAM33 in asthma pathophysiology . Expression of ADAM33 is up‐regulated in airway smooth muscles, fibroblasts, and less frequently airway epithelium of patients with asthma.…”

“…The exact mechanisms underlying these associations remain unknown; however, the soluble form of ADAM33 (sADAM33) may be involved. sADAM33, which is increased in bronchoalveolar fluid of patients with asthma, is efficiently released by transforming growth factor‐β 2 , is catalytically active, promotes angiogenesis in the human lung tissue, and induces airway remodelling, which may provide the “soil” for type‐2 inflammation and airway hyperresponsiveness . Potential interactions between ADAM33 and α catenin, an important protein in airway epithelial barrier function, may also contribute to susceptibility to asthma exacerbation.…”