阿奇霉素通过靶向葡萄糖调节蛋白 78（GRP78）的未折叠蛋白反应成分来减轻类风湿性关节炎的严重程度。
Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of glucose-regulated protein 78 (GRP78).
机构信息
Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China.
出版信息
Br J Pharmacol. 2022 Mar;179(6):1201-1219. doi: 10.1111/bph.15714. Epub 2021 Dec 2.
BACKGROUND AND PURPOSE
Azithromycin is a macrolide antibiotic with anti-inflammatory properties. We aim to substantiate the treatment potential of azithromycin in rheumatoid arthritis.
EXPERIMENTAL APPROACH
Gene expression profiles were collected by RNA sequencing and the effects of azithromycin were assessed by in vitro and in vivo assays on the effects of azithromycin-mediated blockade of glucose-regulated protein 78 (GRP78). Anti-inflammatory activity of azithromycin was measured in fibroblast-like synoviocytes from rheumatoid arthritis patients and in collagen-induced arthritis in DBA/1 mice. Characterization of the binding of azithromycin to GRP78 was performed using drug affinity responsive target stability, proteomics and cellular thermal shift assays. Azithromycin-mediated inhibition of GRP78 and its relationship to its anti-arthritic activity was assessed.
KEY RESULTS
Azithromycin reduced proinflammatory factor production, cell migration, invasion and chemoattraction and enhanced apoptosis, reducing the deleterious inflammatory response of rheumatoid arthritis fibroblast-like synoviocytes in vitro. Azithromycin ameliorated the severity of collagen-induced arthritis lesions as efficiently as the TNFα inhibitor etanercept. Transcriptional analyses suggested that azithromycin treatment impairs signalling cascades associated with cholesterol and lipid biosynthesis. GRP78 was identified as a novel target of azithromycin. Azithromycin-mediated activation of the unfolded protein response via the inhibition of GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (ChOP) but also for the activating sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic processes. Furthermore, deletion of GRP78 abolished the anti-arthritic activity of azithromycin.
CONCLUSION AND IMPLICATIONS
These findings indicate that azithromycin can used to treat rheumatoid arthritis.
背景与目的
阿奇霉素是一种具有抗炎特性的大环内酯类抗生素。我们旨在证实阿奇霉素治疗类风湿关节炎的潜力。
实验方法
通过 RNA 测序收集基因表达谱，并通过体外和体内实验评估阿奇霉素对葡萄糖调节蛋白 78（GRP78）介导的阻断作用的影响。在类风湿关节炎患者的成纤维样滑膜细胞和胶原诱导的 DBA/1 小鼠关节炎中测量阿奇霉素的抗炎活性。使用药物亲和反应靶标稳定性、蛋白质组学和细胞热转移测定来表征阿奇霉素与 GRP78 的结合。评估了阿奇霉素对 GRP78 的抑制作用及其与抗关节炎活性的关系。
主要结果
阿奇霉素减少了促炎因子的产生、细胞迁移、侵袭和趋化作用，增强了凋亡，从而减少了类风湿关节炎成纤维样滑膜细胞体外的有害炎症反应。阿奇霉素在改善胶原诱导性关节炎病变的严重程度方面与 TNFα 抑制剂依那西普同样有效。转录分析表明，阿奇霉素治疗会损害与胆固醇和脂质生物合成相关的信号级联。GRP78 被鉴定为阿奇霉素的一个新靶点。阿奇霉素通过抑制 GRP78 活性介导未折叠蛋白反应的激活，不仅需要诱导 C/EBP 同源蛋白（ChOP）的表达，还需要激活固醇调节元件结合蛋白（SREBP）及其靶向基因，这些基因参与胆固醇和脂质生物合成过程。此外，GRP78 的缺失消除了阿奇霉素的抗关节炎活性。
结论与意义
这些发现表明阿奇霉素可用于治疗类风湿关节炎。
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