Abstract
HAS2 is a member of the gene family encoding the hyaluronan synthase 2, which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for increased susceptibility to adult asthma. However, whether HAS2 dysfunction affects airway remodeling and steroid insensitivity is still limited. Therefore, this study aimed to clarify the Has2 dysfunction, triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Has2 heterozygous-deficient (Has2 +/−) mice and their wild-type littermates have been evaluated in a model of chronic ovalbumin (OVA) sensitization and challenge. Mice present a higher sensitivity to OVA and higher IL-17 release as well as eosinophilic infiltration. RNA sequencing demonstrated the downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2 +/−-OVA mice. The combined treatment with anti-IL-17A antibody and dexamethasone reduces steroid insensitivity in Has2 +/−-OVA mice. Has2 attenuation worsens eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling and could potentially be exploited for their therapeutic benefits in patients with asthma.
Highlights
Airway remodeling is an important feature of asthma characterized by goblet cell hyperplasia, subepithelial collagen, and smooth muscle hyperplasia and is known to play a role in persistent airflow obstruction [1]
These results supported the hypothesis that the expression level of HAS2 gene (Has2) mRNA in Has2+/− mice was downregulated during chronic eosinophilic airway inflammation, and Has2 dysfunction impaired the HMWHA production
Our previous study on acute OVA stimulation reported a significant decrease of Has2 mRNA level in the lungs of Has2+/− mice, high-molecular-weight hyaluronan (HMW-HA) levels were increased in both wild type (WT) and Has2+/− mice that might be affected by Has1 at the early phase of OVA stimulation [5, 18, 19]
Summary
Airway remodeling is an important feature of asthma characterized by goblet cell hyperplasia, subepithelial collagen, and smooth muscle hyperplasia and is known to play a role in persistent airflow obstruction [1]. Because airway remodeling is minimally affected by current treatments, prevention of accelerated airway remodeling is one of the important therapeutic targets of asthma [2]. Our previous genome-wide association study reported that hyaluronan synthase 2 gene (HAS2) is a novel candidate gene for susceptibility to adult asthma [3]. Hyaluronan (HA) is an integral component of the extracellular matrix [4]. HA synthases synthesize large HA polymers of various sizes.
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