Delayed microglial activation associated with the resolution of neuroinflammation in a mouse model of sublethal endotoxemia-induced systemic inflammation.
Delayed microglial activation associated with the resolution of neuroinflammation in a mouse model of sublethal endotoxemia-induced systemic inflammation.
复制标题
DOI：
10.1016/j.toxrep.2022.06.015
复制
发表时间：
2022
影响因子：
--
通讯作者：
Hasegawa-Ishii, Sanae
中科院分区：
文献类型：
--
作者：
Shimada, Atsuyoshi;Murata, Makiko;Aoyagi, Sayaka;Asano, Hinami;Obara, Aki;Hasegawa-Ishii, Sanae
全身性炎症影响大脑功能。在我们以前的研究中，将脂多糖（LPS）以亚致死剂量腹腔注射到小鼠体内，脉络丛巨噬细胞产生白细胞介素-1 β并刺激邻近的基质细胞。活化的基质细胞刺激脉络丛上皮细胞，然后脉络丛上皮衍生的细胞因子进入脑实质并刺激星形胶质细胞。刺激的星形胶质细胞然后产生细胞因子，如CCL 11，CXCL 10和G-CSF，并改变脑实质微环境。然而，改变的大脑微环境对其他脑细胞的影响仍有待确定。在本研究中，我们假设小胶质细胞被激活，以响应星形胶质细胞诱导的脑微环境的变化。使用经腹腔内注射LPS处理的小鼠的脑，Luminex多重细胞因子免疫测定揭示了在全身性LPS攻击后48 h海马CCL 11、CXCL 10和G-CSF浓度增加。LPS注射后72 h，检测的所有细胞因子浓度均恢复至对照水平，表明神经炎症消退。免疫组化结果显示，LPS刺激后48 h，小鼠小胶质细胞明显肥大。使用磁激活细胞分选从脑中分离小胶质细胞后，用实时逆转录酶-聚合酶链反应进行基因表达测定。与其他脑细胞相比，分离的小胶质细胞表现出更高的CCL 11、CXCL 10和G-CSF受体基因表达。从小鼠脑中分离的小胶质细胞在48小时后，全身LPS攻击表现出M2样表型。总之，在亚致死性内毒素血症诱导的全身性炎症小鼠模型中，星形胶质细胞反应后发生小胶质细胞肥大，肥大的小胶质细胞向M2样表型极化，并参与神经炎症的消退。在亚致死性内毒素血症小鼠模型中，星形胶质细胞反应后发生小胶质细胞肥大。星形胶质细胞衍生的细胞因子激活小胶质细胞向M2样表型分化。肥大的小胶质细胞参与神经炎症的消退。
Systemic inflammation affects brain functions. In our previous study in which lipopolysaccharide (LPS) was injected intraperitoneally into mice at sublethal doses, choroid plexus macrophages produced interleukin-1β and stimulated neighboring stromal cells. Activated stromal cells stimulate choroid plexus epithelial cells, and then choroid plexus epithelium-derived cytokines enter the brain parenchyma and stimulate astrocytes. Stimulated astrocytes then produce cytokines such as CCL11, CXCL10 and G-CSF and change the brain parenchymal microenvironment. However, the effects of an altered brain microenvironment on other brain cells remain to be determined. In the present study, we hypothesized that microglia are activated in response to astrocyte-induced changes in the brain microenvironment. Using the brains of mice treated with intraperitoneal LPS injection, Luminex multiplex cytokine immunoassays revealed increased hippocampal concentrations of CCL11, CXCL10 and G-CSF at 48 h after systemic LPS challenge. The concentrations of all cytokines examined returned to control levels at 72 h after LPS injection, which indicated a resolution of the neuroinflammation. Immunohistochemistry revealed that microglia were hypertrophied in mice at 48 h after systemic LPS challenge. Following isolation of microglial cells from the brain using magnetic-activated cell sorting, gene expression assays were performed with real-time reverse transcriptase-polymerase chain reaction. Isolated microglial cells exhibited much higher gene expression of the receptors for CCL11, CXCL10 and G-CSF than other brain cells. Microglial cells isolated from the brains of mice at 48 h after systemic LPS challenge exhibited the M2-like phenotype. In conclusion, microglial hypertrophy occurs following astrocytic reactions in a mouse model of sublethal endotoxemia-induced systemic inflammation, and hypertrophic microglia are polarized toward the M2-like phenotype and involved in the resolution of neuroinflammation. Microglial hypertrophy occurs following astrocytic reaction in a mouse model of sublethal endotoxemia. Astrocyte-derived cytokines activate microglia to polarize toward the M2-like phenotype. Hypertrophic microglia are involved in the resolution of neuroinflammation.