Interactions Between TLR7 and TLR9 Agonists and Receptors Regulate Innate Immune Responses by Astrocytes and Microglia

Toll样受体7(TLR7)和Toll样受体9(TLR9)是固有免疫反应中的重要介质。它们均定位于内涵体间隔,识别核酸和经过髓样分化因子88(MyD88)传导来的信号。本文分析TLR7和TLR9导致的在中枢神经系统固有免疫反应中起作用的星形胶质细胞和小胶质细胞的活化。TLR7和TLR9激动剂引起星形胶质细胞和小胶质细胞相似的细胞因子反应,但二者仍有区别,小胶质细胞产生抗炎因子IL-10、抗凋亡因子G-CSF及IL-9,但星形胶质细胞不产生。对2种细胞的共刺激研究均显示,TLR7激动剂——咪喹莫特,能浓度依赖性地抑制TLR9激动剂引起的固有免疫反应。令人惊讶的是,这种抑制并非由TLR7介导,因为在TLR7的缺乏的情况下,TLR9激动剂导致的固有免疫反应仍然被抑制。固有免疫反应的抑制也并非由于抑制TLR9激动剂摄取所致。这提示咪喹莫特的抑制效应可能是直接作用,也许是通过阻滞CpG-ODN结合和/或TLR9介导的信号转导所致,从而限制细胞活化。这种拮抗关系也存在于小胶质细胞中的这2类受体之间,TLR7的缺乏导致CpG-ODN刺激的细胞因子反应增强。因此,在胶质细胞中,TLR7及其激动剂对TLR9介导的细胞因子反应有抑制作用。

Toll-like receptors 7 （TLR7） and 9 （TLR9） are important mediators of innate immune responses. Both receptors are located in endosomal compartments, recognize nucleic acids, and signal via Myeloid differentiation factor 88 （MyD88）. In the current study, we analyzed TLR7 and TLR9 induced activation of astrocytes and microglia, two cell types that contribute to innate immune responses in the CNS. TLR7 and TLR9 agonists induced similar eytokine profiles within each cell type. However, there were notable differences in the cytokine profile between astroeytes and microglia, including the production of the anti-inflammatory eytokine IL-10 and antiapoptotie cyto- kines Cr-CSF and IL-9 by microglia but not astrocytes. Costimulation studies demonstrated that the TLR7 agonist, imiquimod, could inhibit TLR9 agonist induced innate immune responses, in both cell types, in a concentration-dependent manner. Surprisingly, this inhibition was not mediated by TLRT, as deficiency in TLR7 did not alter suppression of the TLR9 agonist-indueed responses. The suppression of innate immune responses was also not due to an inhibition of TLR9 agonist uptake. This suggested that imiquimod suppression may be a direct effect, possibly by blocking CpG-ODN binding and/or signaling with TLR9, thus limiting cell activation. An antagonistic relationship was also observed between the two receptors in microglia, With TLR7 deficiency resulting in enhanced cytokine responses to CpG-ODN stimulation. Thus, both TLR7 and its agonist can have inhibitory effects on TLR9-indueed cytokine respohses in glial cells.