Past experiments studying innate immunity in the central nervous system (CNS) utilized microglia obtained from neonatal mouse brain, which differ developmentally from adult microglia. These differences might impact our current understanding of the role of microglia in CNS development, function, and disease. Cytokine protein secretion was compared in ex vivo P3 and adult microglial cultures after exposure to agonists for three different toll-like receptors (TLR4, lipopolysaccharide [LPS]; TLR7, imiquimod [IMQ]; and TLR9, CpG Oligodeoxynucleotide [CpG-ODN] 1585). In addition, changes in inflammatory gene expression in ex vivo adult microglia in response to the TLR agonists was assessed. Furthermore, in vivo experiments evaluated changes in gene expression associated with inflammation and TLR signaling in brains of mice with or without treatment with PLX5622 to reduce microglia. Ex vivo adult and P3 microglia increased cytokine secretion when exposed to TLR4 agonist LPS and to TLR7 agonist IMQ. However, adult microglia decreased expression of numerous genes after exposure to TLR 9 agonist CpG-ODN 1585. In contrast, in vivo studies indicated a core group of inflammatory and TLR signaling genes increased when each of the TLR agonists was introduced into the CNS. Reducing microglia in the brain led to decreased expression of various inflammatory and TLR signaling genes. Mice with reduced microglia showed extreme impairment in upregulation of genes after exposure to TLR7 agonist IMQ. Cultured adult microglia were more reactive than P3 microglia to LPS or IMQ exposure. In vivo results indicated microglial influences on neuroinflammation were agonist specific, with responses to TLR7 agonist IMQ more dysregulated in mice with reduced microglia. Thus, TLR7-mediated innate immune responses in the CNS appeared more dependent on the presence of microglia. Furthermore, partial responses to TLR4 and TLR9 agonists in mice with reduced microglia suggested other cell types in the CNS can compensate for their absence.

中文翻译：

---

在离体小胶质细胞培养和使用减少小胶质细胞的小鼠体内模型中用 Toll 样受体激动剂刺激后的先天免疫反应

过去研究中枢神经系统（CNS）先天免疫的实验利用了从新生小鼠脑中获得的小胶质细胞，其在发育上与成年小胶质细胞不同。这些差异可能会影响我们目前对小胶质细胞在 CNS 发育、功能和疾病中的作用的理解。在暴露于三种不同 toll 样受体（TLR4，脂多糖 [LPS]；TLR7，咪喹莫特 [IMQ]；和 TLR9，CpG 寡脱氧核苷酸 [CpG-ODN] 1585 的激动剂后，在体外 P3 和成人小胶质细胞培养物中比较细胞因子蛋白分泌）。此外，还评估了体外成年小胶质细胞对 TLR 激动剂的反应中炎症基因表达的变化。此外，体内实验评估了用或不用 PLX5622 治疗以减少小胶质细胞的小鼠大脑中与炎症和 TLR 信号传导相关的基因表达变化。体外成人和 P3 小胶质细胞在暴露于 TLR4 激动剂 LPS 和 TLR7 激动剂 IMQ 时会增加细胞因子分泌。然而，成年小胶质细胞在暴露于 TLR 9 激动剂 CpG-ODN 1585 后会降低许多基因的表达。相反，体内研究表明，当将每种 TLR 激动剂引入 CNS 时，一组核心的炎症和 TLR 信号基因增加。减少大脑中的小胶质细胞导致各种炎症和 TLR 信号基因的表达减少。小胶质细胞减少的小鼠在暴露于 TLR7 激动剂 IMQ 后，基因上调表现出极大的损害。培养的成人小胶质细胞比 P3 小胶质细胞对 LPS 或 IMQ 暴露更具反应性。体内结果表明，小胶质细胞对神经炎症的影响是激动剂特异性的，在小胶质细胞减少的小鼠中，对 TLR7 激动剂 IMQ 的反应更加失调。因此，CNS 中 TLR7 介导的先天免疫反应似乎更依赖于小胶质细胞的存在。此外，小胶质细胞减少的小鼠对 TLR4 和 TLR9 激动剂的部分反应表明，中枢神经系统中的其他细胞类型可以弥补它们的缺失。