Involvement of N-type Ca2+ channel in microglial activation and its implications to aging-induced exaggerated cytokine response
Involvement of N-type Ca2+ channel in microglial activation and its implications to aging-induced exaggerated cytokine response
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DOI：
10.1016/j.ceca.2019.102059
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发表时间：
2019-09-01
期刊：
影响因子：
4
通讯作者：
Tanabe, Tsutomu
中科院分区：
文献类型：
--
作者：
Huntula, Soontaraporn;Saegusa, Hironao;Tanabe, Tsutomu
电压依赖性钙通道（VDCC）通常被认为仅在可兴奋细胞中有活性。然而，我们最近报道，N型VDCC（Cav2.2）在病理条件下可以在非兴奋细胞中发挥功能。在本研究中，我们发现Cav2.2通道在生理小胶质细胞激活过程中也有功能。通过使用小鼠小胶质细胞系（MG 6），我们研究了Cav2.2阻滞剂对MG 6细胞活化的影响，当用脂多糖（LPS）/干扰素γ（IFN γ）或白细胞介素-4（IL-4）处理时。因此，阻断Cav2.2的激活增强了所谓的小胶质细胞的替代激活过程（向神经保护性M2小胶质细胞的转变），而不改变向神经炎性M1小胶质细胞转变的功效。这种增强的M2转换涉及转录因子缺氧诱导因子2（HIF-2）的激活，因为HIF-2的特异性阻断剂完全消除了这种增强。然后，我们研究了Cav2.2激活是否参与了衰老相关的神经炎症。使用小胶质细胞的原代培养，我们发现，小胶质细胞M1过渡的功效增强，但M2过渡减少老化，与一般的概念，即老化诱导增强神经炎症。最后，我们在这里表明，适度阻断Cav2.2在小胶质细胞中的表达恢复了这种年龄依赖性的减少小胶质细胞M2转变，并减少了衰老诱导的夸张的细胞因子反应，如从小胶质细胞特异性Cav2.2缺陷小鼠的抑郁样行为的快速恢复所揭示的。这些结果表明，小胶质细胞Cav2.2通道在衰老相关的神经炎症中起关键作用。
Voltage-dependent calcium channel (VDCC) is generally believed to be active only in excitable cells. However, we have reported recently that N-type VDCC (Cav2.2) could become functional in non-excitable cells under pathological conditions. In the present study, we show that Cav2.2 channels are also functional in physiological microglial activation process. By using a mouse microglial cell line (MG6), we examined the effects of a Cav2.2 blocker on the activation of MG6 cells, when treated with lipopolysaccharide (LPS) / interferon gamma (IFN gamma) or with interleukin-4 (IL-4). As a result, blocking the activation of Cav2.2 enhanced so-called alternative activation process of microglia (transition to neuroprotective M2 microglia) without changing the efficacy of the transition to neuroinflammatory M1 microglia. This enhanced M2 transition involved the activation of a transcription factor hypoxia inducible factor 2 (HIF-2), since a specific blocker of HIF-2 completely abolished this enhancement. We then examined whether Cav2.2 activation was involved in aging-related neuroinflammation. Using primary culture of microglia, we found that the efficacy of microglial M1 transition was enhanced but that M2 transition was reduced by aging, in agreement with a general notion that aging induces enhanced neuroinflammation. Finally, we show here that the moderate blockade of Cav2.2 expression in microglia restores this age-dependent reduction of microglial M2 transition and reduces the aging-induced exaggerated cytokine response, as revealed by a fast recovery from depressive-like behaviors in microglia-specific Cav2.2 deficient mice. These results suggest a critical role for microglial Cav2.2 channel in the aging-related neuroinflammation.