TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia:: A critical role of IFN-β as a decision maker
TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia:: A critical role of IFN-β as a decision maker
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DOI：
10.4049/jimmunol.174.10.6467
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发表时间：
2005-05-15
影响因子：
4.4
通讯作者：
Suk, K
中科院分区：
文献类型：
--
作者：
Jung, DY;Lee, H;Suk, K
TLR在识别进化上保守的病原体相关分子模式如LPS和脂肽后介导不同的信号传导。已知TLR 2和TLR 4两者都触发保护性免疫应答以及细胞凋亡。在这项研究中，我们提出的证据表明，TLR 4，而不是TLR 2，介导的激活小胶质细胞的自动调节凋亡。脑小胶质细胞在用TLR 4配体（LPS）刺激后发生凋亡，但不经历TLR 2配体（Pam（3）Cys-Ser-Lys（4）、肽聚糖和脂磷壁酸）刺激。基于使用TLR 2缺陷或TLR 4突变小鼠和TLR显性阴性突变体的研究，我们还证明了TLR 4而不是TLR 2是小胶质细胞凋亡所必需的。小胶质细胞中TLR 2和TLR 4信号传导之间的关键差异是IFN调节因子-3（IRF-3）激活，随后是IFN-β表达：而TLR 4激动剂诱导IRF-3/IFN-β途径的激活，而TLR 2不诱导。然而，TLR 2和TLR 4激动剂均强烈诱导小胶质细胞中NF-κ B活化和NO产生。针对IFN-β的中和Ab减弱TLR 4介导的小胶质细胞凋亡。然而，单独的IFN-β不诱导显著的细胞死亡。同时，TLR 2激活在IFN-β的帮助下诱导小胶质细胞凋亡，表明IRF-3激活后IFN-β的产生决定了TLR信号传导的致瘤作用。TLR 4介导的小胶质细胞凋亡由MyD 88和Toll/IL-1 R结构域诱导的IFN-β介导，并且与caspase-11和-3活化相关，而不是Fas相关死亡结构域蛋白/caspase-8途径。综上所述，TLR 4似乎通过自分泌/旁分泌IFN-β的产生发出小胶质细胞凋亡的信号，其可以作为凋亡敏化剂。
TLRs mediate diverse signaling after recognition of evolutionary conserved pathogen-associated molecular patterns such as LPS and lipopeptides. Both TLR2 and TLR4 are known to trigger a protective immune response as well as cellular apoptosis. In this study, we present evidence that TLR4, but not TLR2, mediates an autoregulatory apoptosis of activated microglia. Brain microglia underwent apoptosis upon stimulation with TLR4 ligand (LPS), but not TLR2 ligands (Pam(3)Cys-Ser-Lys(4), peptidoglycan, and lipoteichoic acid). Based on studies using TLR2-deficient or TLR4 mutant mice and TLR dominant-negative mutants, we also demonstrated that TLR4, but not TLR2, is necessary for microglial apoptosis. The critical difference between TLR2 and TLR4 signalings in microglia was IFN regulatory factor-3 (IRF-3) activation, followed by IFN-beta expression: while TLR4 agonist induced the activation of IRF-3/IFN-beta pathway, TLR2 did not. Nevertheless, both TLR2 and TLR4 agonists strongly induced NF-KB activation and NO production in microglia. Neutralizing Ab against IFN-beta attenuated TLR4-mediated microglial apoptosis. IFN-beta(3 alone, however, did not induce a significant cell death. Meanwhile, TLR2 activation induced microglial apoptosis with help of IFN-beta(3, indicating that IFN-beta production following IRF-3 activation determines the apoptogenic action of TLR signaling. TLR4-mediated microglial apoptosis was mediated by MyD88 and Toll/IL-1R domain-containing adaptor-inducing IFN-beta, and was associated with caspase-11 and -3 activation rather than Fas-associated death domain protein/caspase-8 pathway. Taken together, TLR4 appears to signal a microglial apoptosis via autocrine/paracrine IFN-beta production, which may act as an apoptotic sensitizer.