Non-PKC DAG/phorbol-ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II mediated myelin phagocytosis but cPKC, PI3K, and PLCγ activate myelin phagocytosis by both
Non-PKC DAG/phorbol-ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II mediated myelin phagocytosis but cPKC, PI3K, and PLCγ activate myelin phagocytosis by both
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DOI：
10.1002/glia.20304
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发表时间：
2006-04-01
期刊：
影响因子：
6.2
通讯作者：
Rotshenker, S
中科院分区：
文献类型：
--
作者：
Cohen, G;Makranz, C;Rotshenker, S
补体受体 3 (CR3/MAC-1)、清道夫受体 AI/ II (SRAI/II) 和 Fc γ 受体 (Fc γ R) 可介导巨噬细胞和小胶质细胞中的髓磷脂吞噬作用。矛盾的是，中枢神经系统轴突损伤后，这些受体表达，但髓磷脂不被吞噬，这表明吞噬作用受到有效和低效状态之间的调节。在目前的工作中，我们重点关注 CR3/MAC-1 和 SRAI/II 介导的髓磷脂吞噬作用。 CR3/MAC-1 和 SRAI/II 的吞噬作用被 cPKC 抑制剂 Go-6976、通用 PKC 抑制剂 Ro-318220 和 calphostin-C 以及 BAPTA/AM 抑制，BAPTA/AM 螯合 cPKC 激活所需的细胞内 Ca2+。因此建议通过 cPKC 进行信号传导/激活。 PMA 模拟二酰基甘油 (DAG) 作为 cPKC、新型 PKC (nPKC) 和非 PKC DAG 驱动分子的激活剂，对 CR3/MAC-1 和 SRAI/II 的吞噬作用产生剂量依赖性双重作用，即低浓度时增强，高浓度时抑制。通过将抑制浓度的 PMA 与 PKC 抑制剂 Go-6976 或 Ro-318220 组合，CR3/MAC-1 对吞噬作用的抑制得到增强，表明 PMA/DAG 驱动的非 PKC 分子具有抑制作用。相反，通过将抑制浓度的 PMA 与 cPKC 抑制剂 Go-6976 结合使用，SRAI/II 对吞噬作用的抑制得到增强，但与通用 PKC 抑制剂 Ro-318220 结合使用则没有增强，这表明 nPKC 具有抑制作用。 CR3/MAC-1 和 SRAI/II 的吞噬作用进一步被 PI3K 抑制剂渥曼青霉素、LY-294002 和 PLC gamma 抑制剂 U-73122 抑制。总而言之，我们的观察表明 CR3/MAC-1 和 SRAI/II 介导的髓磷脂吞噬作用共同受到 PI3K、PLC gamma 和 cPKC 的激活。然而，两者的不同之处在于，非 PKC DAG 驱动的分子抑制 CR3/MAC-1 介导的吞噬作用，而 nPKC 抑制 SRAI/II 介导的吞噬作用。这些信号传导步骤中的每一个都可以针对在有效和低效状态之间调节CR3/MAC-1和/或SRAI/II介导的吞噬作用。 (C) 2005 Wiley-Liss, Inc.
Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/ II (SRAI/II), and Fc gamma-receptor (Fc gamma R) can mediate myelin phagocytosis in macrophages and microglia. Paradoxically, after injury to CNS axons these receptors are expressed but myelin is not phagocytosed, suggesting that phagocytosis is subject to regulation between efficient and inefficient states. In the present work, we focus on CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis. Phagocytosis by CR3/MAC-1 and SRAI/II was inhibited by cPKC inhibitor Go-6976, general-PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM, which chelates intracellular Ca2+ required for cPKC activation. Signaling/activation by cPKC are thus suggested. PMA, which mimics diacylglycerol (DAG) as an activator of cPKC, novel-PKC (nPKC), and non-PKC DAG-driven molecule(s), produced a dose-dependent dual effect on phagocytosis by CR3/MAC-1 and SRAI/II, i.e., augmentation at low concentrations and inhibition at high concentrations. Inhibition of phagocytosis by CR3/MAC-1 was enhanced by combining inhibiting concentrations of PMA with PKC inhibitors Go-6976 or Ro-318220, suggesting inhibition by PMA/ DAG-driven non-PKC molecule(s). In contrast, inhibition of phagocytosis by SRAI/II was enhanced by combining inhibiting concentrations of PMA with cPKC inhibitor Go-6976 but not with general-PKC inhibitor Ro-318220, suggesting inhibition by nPKC. Phagocytosis by CR3/MAC-1 and SRAI/II was further inhibited by PI3K inhibitors wortmannin and LY-294002 and PLC gamma inhibitor U-73122. Altogether, our observations suggest that CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis share activation by PI3K, PLC gamma and cPKC. The two differ, however, in that non-PKC DAG-driven molecule(s) inhibit CR3/MAC-1-mediated phagocytosis, whereas nPKC inhibit SRAI/II-mediated phagocytosis. Each of these signaling steps may be targeted for regulating CR3/ MAC-1 and/or SRAI/II-mediated phagocytosis between efficient and inefficient states. (C) 2005 Wiley-Liss, Inc.