Sult2b1 deficiency exacerbates ischemic stroke by promoting pro-inflammatory macrophage polarization in mice.
Sult2b1 deficiency exacerbates ischemic stroke by promoting pro-inflammatory macrophage polarization in mice.
复制标题
Sult2b1缺陷通过促进小鼠促炎巨噬细胞极化加剧缺血性中风
作者：
Wang Y;Jin H;Wang Y;Yao Y;Yang C;Meng J;Tan X;Nie Y;Xue L;Xu B;Zhao H;Wang F
基本原理：中风是世界范围内导致人类死亡的主要原因。脑缺血损伤导致无菌神经炎症，直接决定患者的康复。作为大脑的主要组成部分，脂质在中风后发生了显著变化。硫酸胆固醇是一种天然存在的胆固醇类似物，可以直接调节免疫细胞的激活，表明胆固醇代谢产物可能参与了神经炎症。磺基转移酶家族2b成员1(Sult2b1)是催化合成硫酸胆固醇的关键酶。本研究旨在探讨Sult2b1和胆固醇硫酸盐在缺血性卒中后神经炎症中的作用。方法和结果：用Sult2b1-/-和野生型小鼠建立大脑中动脉一过性闭塞模型。我们的数据显示，Sult2b1-/-小鼠有更大的梗塞和更差的神经评分。为了确定免疫细胞是否与Sult2b1-/-小鼠恶化的卒中结局有关，我们进行了骨髓移植、免疫细胞去除和过继单核细胞移植。结合CytoF和免疫荧光技术，我们证明了卒中后，外周血单核细胞来源的巨噬细胞是促进Sult2b1-/-小鼠促炎状态的主要细胞类型。利用原代骨髓来源的巨噬细胞，我们发现在正常和缺氧缺糖条件下，胆固醇可以通过调节烟酰胺腺嘌呤二核苷酸磷酸(NADPH)和活性氧物种(ROS)的水平以及激活AMP激活的蛋白激酶(AMPK)-cAMP反应元件结合蛋白(CREB)信号通路来减轻巨噬细胞的促炎极化。结论：Sult2b1-/-促进巨噬细胞极化进入促炎状态。这一趋势可以通过添加硫酸胆固醇来减弱，硫酸胆固醇通过代谢调节促进巨噬细胞极化进入抗炎状态。在这项研究中，我们建立了缺血性卒中后巨噬细胞极化过程中的炎症-代谢轴。
Rationale: Stroke is a leading causes of human death worldwide. Ischemic damage induces the sterile neuroinflammation, which directly determines the recovery of patients. Lipids, a major component of the brain, significantly altered after stroke. Cholesterol sulfate, a naturally occurring analog of cholesterol, can directly regulate immune cell activation, indicating the possible involvement of cholesterol metabolites in neuroinflammation. Sulfotransferase family 2b member 1 (Sult2b1) is the key enzyme that catalyzes the synthesis of cholesterol sulfate. This study aimed to investigate the function of Sult2b1 and cholesterol sulfate in the neuroinflammation after ischemic stroke. Methods and Results: Sult2b1-/- and wild-type mice were subjected to transient middle cerebral artery occlusion. Our data showed that Sult2b1-/- mice had larger infarction and worse neurological scores. To determine whether immune cells were involved in the worsening stroke outcome in Sult2b1-/- mice, bone marrow transplantation, immune cell depletion, and adoptive monocyte transfer were performed. Combined with CyTOF and immunofluorescence techniques, we demonstrated that after stroke, the peripheral monocyte-derived macrophages were the dominant cell type promoting the pro-inflammatory status in Sult2b1-/-mice. Using primary bone marrow-derived macrophages, we showed that cholesterol sulfate could attenuate the pro-inflammatory polarization of macrophages under both normal and oxygen-glucose deprivation conditions by regulating the levels of nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species (ROS), and activating the AMP-activated protein kinase (AMPK) - cAMP responsive element-binding protein (CREB) signaling pathway. Conclusions: Sult2b1-/- promoted the polarization of macrophages into pro-inflammatory status. This trend could be attenuated by adding cholesterol sulfate, which promotes the polarization of macrophages into anti-inflammatory status by metabolic regulation. In this study, we established an inflammation-metabolism axis during the macrophage polarization after ischemic stroke.