NLRP3 inflammasome activation contributes to acute liver injury caused by CVA6 infection in mice.

IF 3.4 3区 医学 Q2 INFECTIOUS DISEASES BMC Infectious Diseases Pub Date : 2024-11-05 DOI:10.1186/s12879-024-10136-2
Yaqi Xie, Quanman Hu, Guangcai Duan, Fang Wang, Feifei Feng, Dong Li, Wenjie Jiang, Wangquan Ji, Peiyu Zhu, Xiaolong Zhang, Jinzhao Long, Huifen Feng, Haiyan Yang, Shuaiyin Chen, Yuefei Jin
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Abstract

Background: Coxsackievirus (CV) A6 has emerged as an important causative agent in global outbreaks of hand, foot, and mouth disease (HFMD), which typically presents as a mild illness with a large generalized rash, herpes. However, some patients can develop encephalitis, pneumonia, myocarditis and liver injury. Our previous study took the view that CVA6 could replicate in mouse liver, leading to acute liver injury; however, the precise underlying mechanism remains elusive.

Methods: 10-day-old wild-type (WT, C57BL/6J) and NLRP3 knock-out (KO) mice were intraperitoneal (i.p.) inoculated with a lethal dose of the CVA6 strain. The muscle homogenate supernatant from normal mice was used to inoculate mock-infected mice. At 5 days post infection (dpi), the mouse liver was taken out for histopathological analyses and molecular biology experiments.

Results: Our in vivo experiments demonstrated that CVA6 caused severe liver injury in mice, as evidenced by pathological changes in liver slices, elevated liver injury markers (e.g., AST, ALT, LDH) and pro-inflammatory cytokines (e.g., IL-6, MCP-1, TNF-α, IL-1β). Further results revealed the activation of NLRP3 inflammasome characterized by the increase in the expression of NLRP3, Cleaved-Casp-1 (p20), mature IL-1β and IL-18. Importantly, upon CVA6 infection, NLRP3 KO mice exhibited attenuated pathological damage and reduced levels of pro-inflammatory cytokines production (e.g., TNF-α and IL-1β) compared with WT mice. Finally, increased levels of blood ALT, AST, LDH were strongly correlated with the severity of CVA6 patients.

Conclusion: Collectively, our findings suggest that the activation of NLRP3 inflammasome is involved in CVA6 infection-induced acute liver injury, providing novel insights into CVA6 infection associated adverse clinical outcomes.

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NLRP3炎症小体活化是CVA6感染小鼠造成急性肝损伤的原因之一。
背景:柯萨奇病毒(CV)A6 已成为全球爆发的手足口病(HFMD)的重要致病因子,手足口病通常表现为轻微疾病,伴有大面积全身性皮疹和疱疹。然而,有些患者会发展成脑炎、肺炎、心肌炎和肝损伤。我们之前的研究认为,CVA6可在小鼠肝脏中复制,导致急性肝损伤;然而,其确切的内在机制仍难以确定。方法:给10天大的野生型(WT,C57BL/6J)和NLRP3基因敲除(KO)小鼠腹腔注射致死剂量的CVA6菌株。正常小鼠的肌肉匀浆上清液用于接种模拟感染小鼠。感染后 5 天,取出小鼠肝脏进行组织病理学分析和分子生物学实验:我们的体内实验表明,CVA6 会造成小鼠严重的肝损伤,表现为肝切片的病理变化、肝损伤标志物(如 AST、ALT、LDH)和促炎细胞因子(如 IL-6、MCP-1、TNF-α、IL-1β)的升高。进一步的结果显示,NLRP3 炎性体被激活,其特征是 NLRP3、裂解-Casp-1(p20)、成熟 IL-1β 和 IL-18 的表达增加。重要的是,与 WT 小鼠相比,NLRP3 KO 小鼠在感染 CVA6 后病理损伤减轻,促炎细胞因子(如 TNF-α 和 IL-1β)产生水平降低。最后,血液中 ALT、AST 和 LDH 水平的升高与 CVA6 患者的严重程度密切相关:总之,我们的研究结果表明,NLRP3 炎性体的激活参与了 CVA6 感染诱导的急性肝损伤,为 CVA6 感染相关不良临床结局提供了新的见解。
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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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