Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.
Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Glia. 2021 Jul;69(7):1694-1708. doi: 10.1002/glia.23996. Epub 2021 Mar 19.
Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca concentration ([Ca ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75 ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca ]i through binding to the p75 , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.
小胶质细胞是固有免疫细胞，在大脑中被激活后会释放包括促炎和抗炎细胞因子、一氧化氮 (NO) 和神经营养因子等物质。细胞内钙离子浓度 ([Ca2+]i) 的升高对于小胶质细胞的功能很重要，例如激活的小胶质细胞释放细胞因子或 NO。脑源性神经营养因子 (BDNF) 是一种神经营养因子，其在小胶质细胞的激活中发挥作用而闻名。有趣的是，前体形式的 proBDNF 和成熟的 BDNF 在大脑中引发相反的神经元反应。成熟的 BDNF 通过上调啮齿动物小胶质细胞表面表达的 TRPC3 通道，诱导持续的细胞内 Ca2+ 升高。此外，TRPC3 通道对于 BDNF 诱导的激活小胶质细胞中 NO 产生的抑制作用很重要。在这项研究中，我们观察到 proBDNF 和成熟 BDNF 对啮齿动物小胶质细胞表面 p75 神经生长因子受体 (p75) 的相对表达具有相反的影响。ProBDNF 通过与 p75 结合诱导 [Ca2+]i 的持续升高，这可能是由 Rac1 激活和啮齿动物小胶质细胞中的 TRPM7 通道介导的。流式细胞术显示 proBDNF 增加了 TRPM7 的相对表面表达。虽然 proBDNF 既不影响促炎和抗炎细胞因子的 mRNA 表达，也不影响吞噬活性，但 proBDNF 增强了 IFN-γ 诱导的 NO 的产生，而 TRPM7 通道可能参与了 proBDNF 诱导的 IFN-γ 介导的 NO 产生的增强。我们提供了直接证据表明，啮齿动物小胶质细胞能够对 proBDNF 作出反应，这对于调节大脑中的炎症反应可能很重要。
