Has2 Regulates the Development of Ovalbumin-Induced Airway Remodeling and Steroid Insensitivity in Mice

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.

Aggrecan and Hyaluronan: The Infamous Cartilage Polyelectrolytes – Then and Now

“…1.5) and is driven by the availability of intracellular glucose taken up by the cell from the interstitial fluid by glucose transporters and its subsequent conversion to Glc6P [36]. UDP-GlcNAc is then synthesized Impaired skeletal development [159,170] Increased airway hypersensity in asthma [233] Has3 (hyaluronan synthase 3) Altered neuronal activity [6] Decreased neointimal hyperplasia [118,231] Increased tumor cell invasion in human mammary parenchymal tissues [140] Hyal1 (hyaluronidase 1) b Accelerated thinning of knee joint cartilage in aging Prolonged fertility [157] Hyal2 (hyaluronidase 2)…”

Common Pathogeneses Underlying Asthma and Chronic Obstructive Pulmonary Disease -Insights from Genetic Studies

“…These terms were thought to be associated with severe asthma and COPD. Furthermore, in a chronic OVA sensitization and challengeinduced asthma model, 22 IL-17A levels in lung homogenates were higher in Has2 heteroknockout OVA mice than in wild-type mice, and Has2 heteroknockout OVA mice showed goblet cell hyperplasia and excessive mucus production. Thus, chronic OVA stimulation induced a characteristic phenotype of airway remodeling through Has2-mediated attenuation of IL-17 and TGF-β signaling.…”