PDF(Pubmed)
Abstract：
MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage. Dynamic cytoskeletal changes accompany phagocytosis. However, whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear. In this study, we investigated the function of acetylated α-tubulin, a stabilized microtubule form, in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo. We first assessed the function of acetylated α-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines. Acetylated α-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis. Moreover, silencing α-tubulin acetyltransferase 1 (ATAT1), a newly discovered α-tubulin acetyltransferase, decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells. Consistent with these findings, in ATAT1-/- mice, we observed increased ionized calcium binding adapter molecule 1 (Iba1) and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage. Additionally, knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma, ultimately improving neurological recovery of mice after intracerebral hemorrhage. These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage. These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.
摘要：
MIcroglia/巨噬细胞介导的红细胞吞噬作用在脑出血后血肿清除中起关键作用。动态细胞骨架变化伴随吞噬作用。然而,这些变化是否以及如何与小胶质细胞/巨噬细胞介导的红细胞吞噬作用相关尚不清楚.在这项研究中,我们研究了乙酰化α-微管蛋白的功能，稳定的微管形式，在体外和体内脑出血后的小胶质细胞/巨噬细胞红细胞吞噬中。我们首先使用与BV2小胶质细胞或RAW264.7巨噬细胞系共培养的原代DiOGFP标记的红细胞评估乙酰化α-微管蛋白在红细胞吞噬作用中的功能。在红细胞吞噬过程中，BV2和RAW264.7细胞中乙酰化α-微管蛋白的表达显着降低。此外，沉默α-微管蛋白乙酰转移酶1（ATAT1），一种新发现的α-微管蛋白乙酰转移酶，BV2和RAW264.7细胞降低了Ac-α-tub水平并增强了红细胞吞噬作用。与这些发现一致，在ATAT1-/-小鼠中，我们观察到血肿周围红细胞的离子化钙结合衔接分子1(Iba1)和Perls阳性小胶质细胞/巨噬细胞吞噬细胞增加,脑出血小鼠血肿体积减少.此外,敲除ATAT1减轻血肿周围神经元凋亡和促炎细胞因子和增加抗炎细胞因子，最终改善脑出血后小鼠的神经功能恢复。这些发现表明，ATAT1缺乏会加速小胶质细胞/巨噬细胞的红细胞吞噬作用和脑出血后的血肿吸收。这些结果为血肿清除机制提供了新的见解，并表明ATAT1是治疗脑出血的潜在靶标。
