Vitamin B-reath easier: vitamin B6 derivatives reduce IL-33 to limit lung inflammation.
Vitamin B-reath easier: vitamin B6 derivatives reduce IL-33 to limit lung inflammation.
复制标题
维生素 B 更容易：维生素 B6 衍生物可降低 IL-33 以限制肺部炎症。
DOI：
10.1038/s41423-023-01076-z
复制
发表时间：
2023
影响因子：
24.1
通讯作者：
Turnquist,HēthR
中科院分区：
文献类型：
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作者：
Turnquist,HēthR
哮喘是一种慢性过敏性肺病，会使气道发炎和收缩[1]。症状包括呼吸急促、咳嗽和喘息，严重哮喘发作时可导致死亡。哮喘给个人、社会和经济带来巨大负担，每年造成约50万人死亡[2]。不幸的是，哮喘的患病率在全球高收入、低收入和中等收入国家都在增加。哮喘的病理生理学涉及肺上皮细胞和局部免疫细胞轴之间的失调关系，这是难以解决的。与哮喘有关的一个突出的上皮免疫途径是上皮来源的细胞因子和损伤信号白细胞介素-33（IL-33）和表达IL-33受体IL-1受体样1（IL 1 RL 1）的局部免疫细胞，通常称为ST 2 [3]。人IL-33是包含两个关键结构域的270个氨基酸的蛋白质（图1A）。第一结构域（氨基酸1-65）促进IL-33的核定位和染色质缔合。第二个结构域（氨基酸112-270）是介导细胞因子活性的IL-1样细胞因子结构域。这些结构域由中心连接区（氨基酸66-111）分隔[4]。IL-33和IL 1 RL 1的遗传变异与对哮喘和过敏性疾病的易感性相关[5-7]，并且靶向IL-33在临床前研究和最近的临床试验中显示出预防和治疗过敏性肺部炎症的前景[8，9] JL-33的适当调节对于避免致命的2型炎症是必不可少的[10]。并且已经确定了多种调节机制。一种主要机制是核隔离，其中IL-33的N-末端结构域将IL-33结合到核中的染色质以隔离IL-33，直到其在坏死、细胞损伤或应激期间通过不太清楚的机制释放（图1 B）。释放的全长IL-33是活性的，并且可以在接头结构域处被蛋白水解切割以产生更具生物活性的“成熟”片段，或通过细胞凋亡半胱天冬酶介导的细胞因子结构域处的切割而失活（图1C）。一旦在细胞外空间中，IL-33通过氧化迅速失活或被可溶性诱饵受体ST 2中和（图1C）[4]。Zhu等人现在已经阐明了一种调节IL-33稳态水平和蛋白质稳定性的新机制，涉及磷酸吡哆醛（PLP），维生素B6的活性形式和保护性泛素化[11]（总结见图2）。一段时间以来，人们已经知道低PLP血液水平在哮喘患者中很常见，补充维生素B6可以减轻哮喘症状的严重程度[12]。在本研究中，比较了哮喘患者（n= 52）和健康对照组（n= 58）血浆中PLP水平，
Asthma is a chronic allergic lung disease that inflames and constricts the airways [1]. Symptoms include shortness of breath, coughing, and wheezing that can lead to death during severe asthma attacks. Asthma imposes substantial personal, societal and economic burdens and causes approximately half a million deaths per year [2]. Unfortunately, the prevalence of asthma is increasing globally in high-, low-, and middle-income countries alike. The pathophysiology of asthma involves a dysregulated relationship between lung epithelial cells and the local immune cell axis that is difficult to resolve. One prominent epithelial-immune pathway implicated in asthma is the epithelial-derived cytokine and injury signal interleukin-33 (IL-33) and local immune cells expressing the IL-33 receptor IL-1 receptor-like 1 (IL1RL1), commonly referred to as ST2 [3]. Human IL-33 is a 270-amino acid protein comprising two key domains (Fig. 1 A). The first domain (amino acids 1-65) facilitates the nuclear localization and chromatin association of IL-33. The second domain (amino acids 112-270) is the IL-1-like cytokine domain that mediates cytokine activities. These domains are separated by a central linker region (amino acids 66-111)[4]. Genetic variations in IL-33 and IL1RL1 are associated with susceptibility to asthma and allergic diseases [5-7], and targeting IL-33 has shown promise in the prevention and treatment of allergic lung inflammation in preclinical studies and recent clinical trials [8, 9].The proper regulation of IL-33 is essential to avoid lethal type 2 inflammation [10], and multiple regulatory mechanisms have been identified. A major mechanism is nuclear sequestration, where the N-terminal domain of IL-33 binds IL-33 to chromatin in the nucleus to sequester IL-33 until it is released during necrosis, cellular damage, or stress through poorly understood mechanisms (Fig. 1 B). Released full-length IL-33 is active and can be proteolytically cleaved at the linker domain to generate more bioactive “mature7 fragments or inactivated through apoptotic caspase-mediated cleavage at the cytokine domain (Fig. 1 C). Once in the extracellular space, IL-33 is rapidly inactivated via oxidization or neutralized by soluble decoy receptor ST2 (Fig. 1 C)[4]. Zhu et al. have now elucidated a new mechanism that regulates IL-33 homeostatic levels and protein stability involving phosphate-pyridoxal (PLP), an active form of vitamin B6, and protective ubiquitination [11](summarized in Fig. 2). It has been known for some time that low PLP blood levels are common in asthmatic patients, and supplementation with vitamin B6 may reduce the severity of asthma symptoms [12]. In the current study, a comparison of PLP levels in the plasma of asthmatic patients (n= 52) and healthy controls (n= 58)