Rapidly activated epidermal growth factor receptor mediates lipopolysaccharide-triggered migration of microglia
Rapidly activated epidermal growth factor receptor mediates lipopolysaccharide-triggered migration of microglia
复制标题
快速激活的表皮生长因子受体介导脂多糖触发的小胶质细胞迁移
DOI：
10.1016/j.neuint.2015.07.007
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发表时间：
2015-11-01
影响因子：
4.2
通讯作者：
Tian, Dai-Shi
中科院分区：
文献类型：
--
作者：
Qu, Wen-Sheng;Liu, Jun-Li;Tian, Dai-Shi
以往的研究表明，表皮生长因子受体（EGFR）参与了小胶质细胞的活化，其特征是细胞形态学改变、细胞因子产生和细胞迁移;小胶质细胞迁移的生化调控是中枢神经系统炎性损伤后潜在的治疗靶点。然而，EGFR在炎症刺激后小胶质细胞运动中的作用仍然未知。在本研究中，发现脂多糖（LPS）在10分钟内触发快速EGFR磷酸化，这是持续在长期刺激的原代小胶质细胞和培养的BV 2小胶质细胞，而且，阻断EGFR磷酸化的AG 1478显着减弱LPS诱导的小胶质细胞的趋化和趋化动力学迁移。此外，LPS可以启动钙振荡在小胶质细胞在活细胞记录过程中，然而，细胞内的钙螯合剂和钙/钙调素依赖性蛋白激酶II的选择性抑制剂，而不是细胞外的钙螯合剂，显着抑制LPS诱导的EGFR磷酸化在BV 2小胶质细胞。由于EGFR不是LPS的传统受体，这些发现表明EGFR的快速磷酸化归因于LPS触发的细胞内钙动员。通过检测EGFR的下游信号，我们进一步证明了细胞外信号调节激酶（ERK）对于EGFR介导的小胶质细胞迁移是必不可少的，因为ERK抑制减弱了LPS或EGF诱导的小胶质细胞的趋化性和趋化动力学迁移。总的来说，这些结果表明，LPS可以通过动员钙活性触发EGFR的快速磷酸化和随后的ERIC激活，这是炎症条件下小胶质细胞迁移的基础。(C)2015爱思唯尔有限公司版权所有。
Previous reports have suggested that epidermal growth factor receptor (EGFR) is involved in microglia activation characterized by cell morphology changes, cytokine production and cell migration; and the biochemical regulation of the microglia migration is a potential therapeutic target following CNS inflammatory damages. However, the role of EGFR in microglia motility after inflammatory stimulation remains unknown. In the present study, lipopolysaccharide (LPS) was found to trigger rapid EGFR phosphorylation within 10 min, which was sustained during long-term stimulation in both primary microglial cells and the cultured BV2 microglial cells, furthermore, blocking EGFR phosphorylation by AG1478 significantly attenuated the LPS-induced chemotactic and chemokinetic migration of microglia. In addition, LPS could initiate calcium oscillation in microglia during live-cell recording, however, an intracellular calcium chelator and a selective inhibitor of calcium/calmodulin-dependent protein kinase II, but not an extracellular calcium chelator, remarkably suppressed the LPS-induced EGFR phosphorylation in BV2 microglia cells. As EGFR is not a traditional receptor for LPS, these findings suggest that the rapid phosphorylation of EGFR is attributed to the LPS-triggered intracellular calcium mobilization. By examining the downstream signals of EGFR, we further proved that extracellular signal-regulated kinase (ERK) is essential for EGFR-mediated microglia migration, because ERK inhibition attenuated the chemotactic and chemokinetic migration of microglia that had been induced by either LPS or EGF. Collectively, these results suggest that LPS could trigger the rapid phosphorylation of EGFR and subsequent ERIC activation through mobilizing calcium activity, which underlies the microglia migration in an inflammatory condition. (C) 2015 Elsevier Ltd. All rights reserved.