Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity,Cell Death & Disease

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Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity
Cell Death & Disease ( IF 8.1 ) Pub Date : 2024-01-12 , DOI: 10.1038/s41419-023-06414-7
Yiwei Feng _{1,

2,

3} , Lishan Lin _{1,

2} , Tengteng Wu _{1,

2,

4} , Yukun Feng _{1,

2,

5} , Fengyin Liang _{1,

2} , Ge Li ₆ , Yongchao Li ₆ , Yalun Guan ₆ , Shuhua Liu ₆ , Yu Zhang ₆ , Guangqing Xu ₇ , Zhong Pei _{1,

2}

Affiliation

AbstractMicroinfarcts are common among the elderly and patients with microinfarcts are more vulnerable to another stroke. However, the impact of microinfarcts on recurrent stroke has yet to be fully understood. The purpose of this study was to explore the negative effects of microinfarcts on recurrent stroke. To achieve this, two-photon laser was used to induce microinfarcts, while photothrombotic stroke was induced on the opposite side. The results showed that microinfarcts led to trained immunity in microglia, which worsened the pro-inflammatory response and ischemic injury in the secondary photothrombotic stroke. Additionally, the study clarified the role of NLRP3 in microglial nuclei, indicating that it interacts with the MLL1 complex through NACHT domain and increases H3K4 methylation, which suggests that NLRP3 is critical in the formation of innate immune memory caused by microinfarcts. Furthermore, the knockout of NLRP3 in microglia alleviated the trained immunity and reduced the harmful effects of microinfarcts on recurrent stroke. This study emphasizes the detrimental effect of trained immunity on recurrent stroke and highlights the critical role of NLRP3 in mediating the formation of this memory, which may offer a potential therapeutic target for mitigating recurrent strokes.

中文翻译：

皮质微梗塞通过 NLRP3 依赖性训练免疫增强复发性缺血性损伤

摘要微梗塞在老年人中很常见，患有微梗塞的患者更容易再次中风。然而，微梗塞对复发性中风的影响尚未完全了解。本研究的目的是探讨微梗塞对复发性中风的负面影响。为了实现这一目标，使用双光子激光诱发微梗塞，同时在另一侧诱发光血栓性中风。结果表明，微梗塞导致小胶质细胞的免疫力受到训练，从而恶化了继发性光血栓性中风中的促炎症反应和缺血性损伤。此外，该研究阐明了NLRP3在小胶质细胞核中的作用，表明其通过NACHT结构域与MLL1复合物相互作用并增加H3K4甲基化，这表明NLRP3在微梗死引起的先天免疫记忆的形成中至关重要。此外，小胶质细胞中NLRP3的敲除减轻了训练有素的免疫力，并减少了微梗塞对复发性中风的有害影响。这项研究强调了训练有素的免疫力对复发性中风的不利影响，并强调了 NLRP3 在介导这种记忆形成中的关键作用，这可能为减轻复发性中风提供潜在的治疗靶点。

更新日期：2024-01-12

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