Department of Neuroscience, Section of Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
J Neurosci Res. 2013 Sep;91(9):1133-42. doi: 10.1002/jnr.23221. Epub 2013 May 17.
Neuroinflammation is required for tissue clearance and repair after infections or insults. To prevent excessive damage, it is crucial to limit the extent of neuroinflammation and thereby the activation of its principal effector cell, microglia. The two main major innate immune cell types in the CNS are astrocytes and microglia. Histone deacetylases (HDACs) have been implicated in regulating the innate inflammatory response, and here we addressed their role in pure astrocyte and microglia cultures. Endogenous HDAC expression levels were determined in microglia and astrocytes and after treatment with lipopolysaccharide (LPS) or LPS and interferon γ (IFNγ). The relative expression level of HDACs was reduced in LPS- or LPS/IFNγ (with the exception of HDAC1 and -7)-stimulated astrocytes and increased in microglia after LPS treatment both in primary cultures and in microglia acutely isolated from LPS-treated mice, so we focused on the inflammatory response in microglia. Primary microglia cultures were treated with LPS in the presence or absence of HDAC inhibitors (HDACi). Expression and release of inflammatory cytokines was determined by quantitative RT-PCR, flow cytometry, and ELISA. HDACi strongly suppressed LPS-induced cytokine expression and release by microglia. Furthermore, expression of M1- and M2-associated activation markers was suppressed, and the migratory behavior of microglia was attenuated. Our findings strongly suggest that HDACi suppress innate immune activation in microglia.
神经炎症是感染或损伤后组织清除和修复所必需的。为了防止过度的损伤，限制神经炎症的程度从而限制其主要效应细胞小胶质细胞的激活至关重要。中枢神经系统中主要的两种固有免疫细胞类型是星形胶质细胞和小胶质细胞。组蛋白去乙酰化酶（HDACs）被认为参与调节固有炎症反应，在这里我们研究了它们在纯星形胶质细胞和小胶质细胞培养物中的作用。在小胶质细胞和星形胶质细胞中以及用脂多糖（LPS）或 LPS 和干扰素 γ（IFNγ）处理后，确定了内源性 HDAC 表达水平。在 LPS 或 LPS/IFNγ（除了 HDAC1 和 -7）刺激的星形胶质细胞中，HDACs 的相对表达水平降低，而在 LPS 处理后的小胶质细胞中增加，无论是在原代培养物中还是在从 LPS 处理的小鼠中急性分离的小胶质细胞中都是如此，因此我们专注于小胶质细胞中的炎症反应。用 LPS 在存在或不存在 HDAC 抑制剂（HDACi）的情况下处理原代小胶质细胞培养物。通过定量 RT-PCR、流式细胞术和 ELISA 测定炎症细胞因子的表达和释放。HDACi 强烈抑制 LPS 诱导的小胶质细胞细胞因子的表达和释放。此外，M1 和 M2 相关激活标志物的表达受到抑制，小胶质细胞的迁移行为减弱。我们的研究结果强烈表明，HDACi 抑制小胶质细胞固有免疫激活。
