Exploring Candesartan, an angiotensin II receptor antagonist, as a novel inhibitor of NLRP3 inflammasome: alleviating inflammation in Neisseria gonorrhoeae infection.

IF 3.4 3区 医学 Q2 INFECTIOUS DISEASES BMC Infectious Diseases Pub Date : 2024-11-22 DOI:10.1186/s12879-024-10208-3
Wen-Yu Lin, Jin-Lian Tsui, Hsiao-Wen Chiu, Wei-Ting Wong, Chun-Hsien Wu, Hsien-Ta Hsu, Chen-Lung Ho, Shan-Pei Yeh, Yerra Koteswara Rao, Ann Chen, Chien-Chun Wang, Chung-Hua Hsu, Oleg V Chernikov, Kuo-Feng Hua, Lan-Hui Li
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Abstract

Background: Gonorrhea, induced by Neisseria gonorrhoeae infection, stands as a prevalent sexually transmitted inflammatory disease globally. Our earlier research illuminated that N. gonorrhoeae-infected macrophages provoke inflammation by activating the intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, a pivotal regulator in inflammatory diseases governing the maturation and secretion of interleukin (IL)-1β and IL-18. Nevertheless, effective therapies addressing N. gonorrhoeae-mediated NLRP3 inflammasome activation and ensuing inflammation are currently lacking. This study delves into the impact of the angiotensin II receptor antagonist Candesartan (CS) on N. gonorrhoeae-infected macrophages.

Methods: The protein expression levels were examined through ELISA and Western blotting. Intracellular H2O2 levels, mitochondrial reactive oxygen species, and mitochondrial membrane integrity were evaluated using targeted fluorescent probes and analyzed via flow cytometry. NF-κB transcriptional activity was assessed using NF-κB reporter cells. LC3-knockdown cells were created using CRISPR/Cas9 technology.

Results: CS effectively inhibits the NLRP3 inflammasome, as indicated by the suppression of caspase-1 activation, IL-1β secretion, NLRP3 release, and the release of apoptosis-associated speck-like protein containing a CARD (ASC) in N. gonorrhoeae-infected J774A.1 macrophages. Additionally, CS selectively impedes IL-6 secretion and iNOS expression in both N. gonorrhoeae-infected J774A.1 and RAW264.7 macrophages. Mechanistic insights uncover the inhibition of NF-κB by CS in N. gonorrhoeae-infected J774A.1 macrophages, while intracellular H2O2 generation, mitogen-activated protein kinases phosphorylation, and mitochondrial damage remain unaffected. Notably, our study highlights that CS-induced autophagy contributes partially to its inhibitory effect on the NLRP3 inflammasome.

Conclusions: These results underscore the potential of CS as an anti-inflammatory drug for the treatment of gonorrhea, addressing a critical unmet medical need in combating N. gonorrhoeae-induced inflammation.

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探索将血管紧张素 II 受体拮抗剂坎地沙坦作为 NLRP3 炎症小体的新型抑制剂:减轻淋病奈瑟菌感染的炎症反应。
背景:由淋病奈瑟菌感染诱发的淋病是全球流行的性传播炎症疾病。我们早前的研究表明,淋病奈瑟菌感染的巨噬细胞通过激活细胞内传感器 NACHT、LRR 和 PYD 结构域含蛋白 3(NLRP3)炎性体引发炎症,NLRP3 炎性体是炎症性疾病的关键调节因子,可调节白细胞介素(IL)-1β 和 IL-18 的成熟和分泌。然而,目前还缺乏有效的疗法来解决淋病介导的 NLRP3 炎性体激活和随之而来的炎症。本研究探讨了血管紧张素 II 受体拮抗剂坎地沙坦(CS)对淋球菌感染的巨噬细胞的影响:方法:通过 ELISA 和 Western 印迹检测蛋白质表达水平。使用靶向荧光探针评估细胞内 H2O2 水平、线粒体活性氧和线粒体膜完整性,并通过流式细胞仪进行分析。使用 NF-κB 报告细胞评估 NF-κB 的转录活性。利用CRISPR/Cas9技术创建了LC3敲除细胞:结果:CS能有效抑制NLRP3炎性体,表现为抑制淋球菌感染的J774A.1巨噬细胞中caspase-1的激活、IL-1β的分泌、NLRP3的释放以及含有CARD的凋亡相关斑点样蛋白(ASC)的释放。此外,CS 还能选择性地抑制淋球菌感染的 J774A.1 和 RAW264.7 巨噬细胞中 IL-6 的分泌和 iNOS 的表达。机理研究揭示了 CS 在淋病感染的 J774A.1 巨噬细胞中对 NF-κB 的抑制作用,而细胞内 H2O2 生成、丝裂原活化蛋白激酶磷酸化和线粒体损伤则不受影响。值得注意的是,我们的研究强调,CS诱导的自噬在一定程度上促进了其对NLRP3炎性体的抑制作用:这些结果凸显了 CS 作为治疗淋病的抗炎药物的潜力,解决了抗淋病引起的炎症这一尚未满足的关键医疗需求。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Infectious Diseases
BMC Infectious Diseases 医学-传染病学
CiteScore
6.50
自引率
0.00%
发文量
860
审稿时长
3.3 months
期刊介绍: BMC Infectious Diseases is an open access, peer-reviewed journal that considers articles on all aspects of the prevention, diagnosis and management of infectious and sexually transmitted diseases in humans, as well as related molecular genetics, pathophysiology, and epidemiology.
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