阻断 NLRP3 和 Th17 在 Balb/c 小鼠中的协调作用可改善 CVB3 诱导的心肌炎的严重程度。

The Severity of CVB3-Induced Myocarditis Can Be Improved by Blocking the Orchestration of NLRP3 and Th17 in Balb/c Mice.

机构信息

Medical Science Laboratory, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545005, China.

Internal Medicine-Cardiovascular Department, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545005, China.

出版信息

Mediators Inflamm. 2021 May 12;2021:5551578. doi: 10.1155/2021/5551578. eCollection 2021.

DOI:10.1155/2021/5551578

PMID:34093086

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8139334/

Abstract

BACKGROUND

The functional characteristics of NLRP3 in the pathogenesis of coxsackievirus B3- (CVB3-) induced viral myocarditis (VMC) have not been fully elucidated, and the targeted therapeutic effect of NLRP3 or its related pathway in VMC has not been reported.

METHOD

In this work, the change patterns of NLRP3- and Th17-related factors were detected during the pathological process of CVB3-induced VMC in Balb/c mice. The correlation between NLRP3 and Th17 cells during the VMC process was analyzed by Spearman test. The coculture system of spleen CD4 T and bone marrow CD11c DC cells was set to explore the orchestration of NLRP3 and Th17 in the pathological development of VMC in vitro. Anti-IL-1 antibody or NLRP3 Balb/c were used to block the NLRP3 pathway indirectly and directly to analyze the NLRP3-targeting therapeutic value.

RESULTS

The change patterns of NLRP3- and Th17-related molecules in the whole pathological process of mouse CVB3-induced VMC were described. Through Spearman correlation analysis, it was confirmed that there was a close correlation between NLRP3 and Th17 cells in the whole pathological process of VMC. And the interaction mode between NLRP3 and Th17 was preliminarily explored in the cell experiment in vitro. Under the intervention of an anti-IL-1 antibody or NLRP3 knockout, the survival rate of the intervention group was significantly improved, the degree of myocardial inflammation and fibrosis was significantly alleviated, and the content of myocardial IL-17 and spleen Th17 was also significantly decreased.

CONCLUSION

Our findings demonstrated a key role of the NLRP3 inflammasome and its close relationship with Th17 in the pathological progression of CVB3-induced VMC and suggested a possible positive feedback-like mutual regulation mechanism between the NLRP3 inflammasome and Th17 in vitro and in the early stage of CVB3 infection. Taking NLRP3 as a new starting point, it provides a new target and idea for the prevention and treatment of CVB3-induced VMC.

摘要

背景

NLRP3 在柯萨奇病毒 B3 （CVB3）诱导的病毒性心肌炎（VMC）发病机制中的功能特征尚未完全阐明，也尚未报道 NLRP3 或其相关途径在 VMC 中的靶向治疗效果。

方法

本工作检测了 Balb/c 小鼠 CVB3 诱导的 VMC 病理过程中 NLRP3 和 Th17 相关因子的变化模式。采用 Spearman 检验分析了 NLRP3 与 Th17 细胞在 VMC 过程中的相关性。通过建立脾 CD4+T 细胞与骨髓 CD11c+DC 细胞共培养体系，体外探讨 NLRP3 与 Th17 在 VMC 病理发生中的协同作用。采用抗 IL-1 抗体或 NLRP3 敲除鼠间接和直接阻断 NLRP3 通路，分析 NLRP3 靶向治疗的价值。

结果

描述了 NLRP3 和 Th17 相关分子在小鼠 CVB3 诱导的 VMC 全病理过程中的变化模式。通过 Spearman 相关性分析，证实了 NLRP3 与 Th17 细胞在 VMC 全病理过程中存在密切相关性。并初步在体外细胞实验中探讨了 NLRP3 与 Th17 的相互作用模式。在抗 IL-1 抗体或 NLRP3 敲除鼠的干预下，干预组的存活率明显提高，心肌炎症和纤维化程度明显减轻，心肌 IL-17 和脾脏 Th17 的含量也明显降低。

结论

本研究结果表明 NLRP3 炎性小体及其与 Th17 的密切关系在 CVB3 诱导的 VMC 病理进展中起关键作用，并提示 NLRP3 炎性小体与 Th17 之间可能存在体外和 CVB3 感染早期的正反馈样相互调节机制。以 NLRP3 为新起点，为防治 CVB3 诱导的 VMC 提供了新的靶点和思路。