<br>Lamin A/C 通过调节细胞增殖和免疫反应介导小胶质细胞活化,Journal of Neuroscience Research

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Lamin A/C 通过调节细胞增殖和免疫反应介导小胶质细胞活化
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2023-11-10 , DOI: 10.1002/jnr.25263
Haotian Liu _{1,

2} , Xinnan Liu ₂ , Shiqi Luo ₂ , Rayna Ma ₂ , Wei Ge ₂ , Shu Meng ₂ , Yanpan Gao _{1,

2}

Affiliation

Lamin A/C 参与巨噬细胞激活和过早衰老（也称为早衰）。作为大脑中常驻的巨噬细胞，小胶质细胞的过度激活会导致大脑炎症，从而促进衰老和脑部疾病。在本研究中，我们使用Lmna ^−/−小鼠、原代小胶质细胞、 Lmna敲除 ( Lmna -KO) 和Lmna敲除 ( Lmna -KD) BV2 细胞系研究了 Lamin A/C 在小胶质细胞激活中的作用及其对早衰的影响。我们发现，当用 LPS 刺激时，所有 Lamin A/C 缺陷模型中的小胶质细胞激活特征，包括细胞增殖、形态变化和促炎细胞因子分泌（IL-1β、IL-6 和 TNF-α）均显着受到抑制。进一步应用基于TMT的定量蛋白质组学和生物信息分析，从蛋白质组水平探讨Lamin A/C调节小胶质细胞活化的机制。结果显示， Lmna ^−/−小胶质细胞的免疫反应和吞噬作用受损。 Stat1 被确定为 Lamin A/C 调节小胶质细胞激活机制中的枢纽蛋白。此外，DNA 复制、染色质组织和 mRNA 加工也被 Lamin A/C 改变，其中 Ki67 履行了主要的中枢功能。 Lamin A/C 是一种机械敏感蛋白，免疫和增殖相关的生物过程也受到机械转导的调节。我们推测 Lamin A/C 介导的机械转导是小胶质细胞激活所必需的。我们的研究提出了一种由 Lamin A/C 介导的小胶质细胞激活的新机制。

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Lamin A/C mediates microglial activation by modulating cell proliferation and immune response

Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna^−/− mice, primary microglia, Lmna knockout (Lmna-KO) and Lmna-knockdown (Lmna-KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL-1β, IL-6, and TNF-α), were significantly suppressed in all Lamin A/C-deficient models when stimulated with LPS. TMT-based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C-regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna^−/− microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune- and proliferation-related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C-mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C.

更新日期：2023-11-10

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