Department of Pediatrics, Qilu Hospital, Shandong University, No. 107, Wen Hua Xi Road, Jinan, 250012, Shandong, China.
The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
Inflammation. 2020 Apr;43(2):701-711. doi: 10.1007/s10753-019-01152-5.
Toll-like receptor 2 (TLR2) regulates the innate immune response of microglia during infection via autophagy. Microglial M1/M2 phenotypic switching after infection could serve as a novel pathogenic mechanism for cerebral infection. Hence, it has important implications for the damage and restoration of neurological function. However, the effect of TLR2-mediated autophagic signaling on microglial phenotypic transition remains unclear. Therefore, we investigated the mechanisms of TLR2-mediated autophagic signaling in the regulation of microglial M1/M2 phenotypes. Using Western blot analysis and immunofluorescence, increased autophagy was observed in peptidoglycan (PGN)-stimulated BV2 cells, while reduced autophagy was observed in TLR2-KO cells. In contrast to the TLR2 antagonist CU-CPT22 group, increased autophagy was observed in the presence of the TLR2 agonist Pam3CSK4, which was associated with a significant increase in expression levels of M1 phenotype biomarkers (CD86, TNF-α, IL-6), higher levels of apoptosis, and decreased expression levels of M2 markers (CD206, IL-10, Arg-1). In the TLR2-KO mice, the expression levels of autophagy-related proteins in CD11b cells were lower than those in CD11b cells in the PGN-injected wild-type mice, and neuronal apoptosis was also reduced, but there were no significant differences compared to the control group. Collectively, our study demonstrates that the inhibition of autophagy or the absence of TLR2 induces microglial polarization towards the M2 phenotype, promotes microglial survival alone, and alleviates the development of neuroinflammation. In summary, TLR2-mediated autophagic signaling contributes to regulating the inflammatory response to activate microglial M1/M2 switching, which affects microglial survival after infection.
Toll 样受体 2 (TLR2) 通过自噬调节感染期间小胶质细胞的固有免疫反应。感染后小胶质细胞 M1/M2 表型转换可作为脑感染的新发病机制。因此，它对神经功能的损伤和恢复具有重要意义。然而，TLR2 介导的自噬信号对小胶质细胞表型转换的影响尚不清楚。因此，我们研究了 TLR2 介导的自噬信号在调节小胶质细胞 M1/M2 表型中的机制。通过 Western blot 分析和免疫荧光，我们观察到肽聚糖 (PGN) 刺激的 BV2 细胞中自噬增加，而 TLR2-KO 细胞中自噬减少。与 TLR2 拮抗剂 CU-CPT22 组相反，TLR2 激动剂 Pam3CSK4 的存在增加了自噬，这与 M1 表型生物标志物（CD86、TNF-α、IL-6）表达水平的显著增加、凋亡水平的升高和 M2 标志物（CD206、IL-10、Arg-1）表达水平的降低有关。在 TLR2-KO 小鼠中，CD11b 细胞中自噬相关蛋白的表达水平低于 PGN 注射野生型小鼠中的 CD11b 细胞，神经元凋亡也减少，但与对照组相比无显著差异。总之，本研究表明，自噬的抑制或 TLR2 的缺失诱导小胶质细胞向 M2 表型极化，促进小胶质细胞的存活，并减轻神经炎症的发展。综上所述，TLR2 介导的自噬信号有助于调节小胶质细胞的炎症反应，激活 M1/M2 转换，影响感染后小胶质细胞的存活。
