Microglia play a complex role in the response to brain injury, with past work showing that these cells can both aid in the recovery from ischemic stroke and exacerbate its pathology. A recent study in Science Advances explores this topic through the chromatin remodeling protein HDAC3, which broadly activates the expression of target genes. The authors surgically induced transient focal cerebral ischemia (tFCI) in wild-type mice and in mice in which Cre–lox recombination enabled selective depletion of Hdac3 in microglia. Mice lacking microglial Hdac3 developed less severe brain lesions and white matter damage and experienced faster motor recovery from tFCI compared to wild-type littermates. Depletion of microglial Hdac3 also limited the emergence of pro-inflammatory CD16⁺ microglia after tFCI without affecting the proliferation of other, anti-inflammatory, microglia. A multi-omic analysis revealed that predicted targets of the transcription factor PU.1 were dysregulated following loss of microglial Hdac3 in mice that underwent tFCI. Consequently, overexpression of PU.1 in Hdac3-lacking microglia partly restored the proliferation of CD16⁺ microglia. Overall, these findings suggest a pathway by which stroke induces HDAC3-mediated chromatin remodeling, thereby activating PU.1 and the rise of pro-inflammatory microglia that complicate recovery from brain injury.

Original reference: Sci. Adv. 10, eade6900 (2024)

小胶质细胞在脑损伤反应中发挥着复杂的作用，过去的研究表明，这些细胞既可以帮助缺血性中风的恢复，也可以加剧其病理学。Science Advances最近的一项研究通过染色质重塑蛋白 HDAC3 探索了这个主题，该蛋白广泛激活靶基因的表达。作者通过手术在野生型小鼠和 Cre- lox重组能够选择性耗尽小胶质细胞中Hdac3的小鼠中诱导短暂性局灶性脑缺血 (tFCI) 。与野生型同窝小鼠相比，缺乏小胶质细胞Hdac3 的小鼠脑部损伤和白质损伤较轻，并且从 tFCI 中的运动恢复更快。小胶质细胞Hdac3的耗竭还限制了 tFCI 后促炎 CD16 ⁺小胶质细胞的出现，而不影响其他抗炎小胶质细胞的增殖。多组学分析显示，在接受 tFCI 的小鼠中，小胶质细胞Hdac3缺失后，转录因子 PU.1 的预测靶标出现失调。因此，PU.1 在缺乏Hdac3的小胶质细胞中过度表达部分恢复了 CD16 ⁺小胶质细胞的增殖。总体而言，这些发现表明中风诱导 HDAC3 介导的染色质重塑的途径，从而激活 PU.1 和促炎性小胶质细胞的增加，从而使脑损伤的恢复变得复杂。

原文参考： Sci.高级​10、eade6900（2024）