Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Biochem Biophys Res Commun. 2020 Jun 25;527(2):553-560. doi: 10.1016/j.bbrc.2020.04.113. Epub 2020 May 15.
A non-histone chromatin-associated protein, high mobility group box 1 (HMGB1), which impairs the airway epithelial barrier, is involved in the induction of airway inflammation in patients with allergy, asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Tricellular tight junctions (tTJs) form at the convergence of bicellular tight junctions (bTJs). Angulin-1/lipolysis-stimulated lipoprotein receptor (LSR) is a novel molecule present at tricellular contacts and contributes to the epithelial barrier and cellular metabolism. Adenosine monophosphate-activated protein kinase (AMPK) is a central metabolic regulator and has a reciprocal association with TJs. In the present study, to examine how HMGB1 contributes to airway epithelial barrier disruption and the cellular metabolism indicated as mitochondrial respiration, bronchial epithelial Calu-3 cells were transfected with siRNAs of angulin-1/LSR or treated with HMGB1 and the relationship between HMGB1 and angulin-1/LSR was investigated. Knockdown of angulin-1/LSR upregulated the expression of the tight junction molecule claudin-2, AMPK activity, and mitochondrial respiration, and downregulated the epithelial barrier. Treatment with HMGB1 downregulated angulin-1/LSR expression and the epithelial barrier, and upregulated claudin-2 expression, AMPK activity and mitochondrial respiration. Treatment with EW-7197, a transforming growth factor-β (TGF-β) type I receptor kinase inhibitor, prevented all the effects of HMGB1 in Calu-3 cells. HMGB1-downregulated angulin-1/LSR induced epithelial barrier disruption via claudin-2 and cellular metabolism via AMPK in airway epithelial Calu-3 cells. The effects of HMGB1 contribute to TGF-β signaling and EW-7197 shows potential for use in therapy for HMGB1-induced airway inflammation.
一种非组蛋白染色质相关蛋白，高迁移率族蛋白 B1（HMGB1），它损害气道上皮屏障，参与诱导过敏、哮喘、慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）患者的气道炎症。三细胞紧密连接（tTJs）在双细胞紧密连接（bTJs）的交汇处形成。Angulin-1/脂肪分解刺激脂蛋白受体（LSR）是一种存在于三细胞接触处的新型分子，有助于上皮屏障和细胞代谢。单磷酸腺苷激活蛋白激酶（AMPK）是一种中央代谢调节剂，与 TJ 有相互关联。在本研究中，为了研究 HMGB1 如何导致气道上皮屏障破坏和细胞代谢（如线粒体呼吸），用 angulin-1/LSR 的 siRNA 转染支气管上皮细胞 Calu-3 或用 HMGB1 处理，研究了 HMGB1 与 angulin-1/LSR 之间的关系。下调 angulin-1/LSR 上调紧密连接分子 Claudin-2 的表达、AMPK 活性和线粒体呼吸，并下调上皮屏障。HMGB1 处理下调 angulin-1/LSR 表达和上皮屏障，并上调 Claudin-2 表达、AMPK 活性和线粒体呼吸。用转化生长因子-β（TGF-β）I 型受体激酶抑制剂 EW-7197 处理可阻止 HMGB1 在 Calu-3 细胞中的所有作用。HMGB1 下调 angulin-1/LSR 通过 Claudin-2 诱导气道上皮细胞 Calu-3 中的上皮屏障破坏，并通过 AMPK 诱导细胞代谢。HMGB1 的作用有助于 TGF-β 信号转导，EW-7197 显示出在治疗 HMGB1 诱导的气道炎症方面的应用潜力。
