천식의 점액 과다분비 조절에서 S1PR4 (sphingosine-1-phosphate receptor 4)의 역할

Abstract

Goblet cell hyperplasia, a key feature of asthmatic airway remodeling, causes excessive mucus production and plugging, worsening asthma symptoms and lung function, especially in severe acute exacerbations and treatment-resistant asthma phenotypes. As current asthma treatments have limited efficacy in addressing goblet cell hyperplasia and mucus hypersecretion, there is a pressing need for targeted therapies that regulate mucin production. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, regulates various cellular processes and S1P levels were elevated in asthma in accordance with the asthma severity. S1P receptor 4 (S1PR4), specifically expressed in immune cells and lungs, is implicated in allergic airway inflammation. Despite reports of decreased S1PR4 expression in asthma and mucin- productive diseases, its precise role in goblet cell hyperplasia and airway remodeling remains elusive. This study aimed to elucidate the impact and mechanisms of the S1PR4 pathway in goblet cell hyperplasia in asthma. At first, we established an inflammation and bronchoconstriction-driven chronic murine asthma remodeling model to study the role of S1PR4 in regulating this process. Mice exposed to methacholine inhalation during ovalbumin (OVA) challenge after OVA sensitization exhibited exacerbated mucin production and collagen deposition in the airways compared to those in the standard OVA-induced asthma model. And then, to elucidate the role of S1PR4 in airway mucin production, we used heterozygous S1PR4 knockout mice to generate the model. Depletion of S1PR4 in these mice further aggravated mucin production and collagen deposition in lung, trachea and bronchi tissues. Micro-CT scans further disclosed more pronounced peribronchial patches and greater airway obstruction in the lungs of mice with S1PR4 depletion in this model. S1PR4 depletion significantly enhanced expression of the mucin genes MUC5AC and MUC5B, and a regulator of mucin genes SPDEF in the remodeled airways. Furthermore, S1PR4 depletion was significantly associated with an increase in the expression of the EGF gene and a decrease in the expression of the WNT2 and WNT7a genes. These findings suggest that the S1PR4 pathway plays a crucial role in regulating goblet cell hyperplasia and mucin production. Upregulating S1PR4 levels in chronic asthmatic remodeling may be a potential therapeutic approach for treating asthma-related goblet cell hyperplasia and mucus hypersecretion. Keywords: Sphingosine-1-phosphate receptor 4, Asthmatic airway remodeling, Goblet cell hyperplasia, Mucin gene