Rocha Sandra M, Saraiva Tatiana, Cristóvão Ana C, Ferreira Raquel, Santos Tiago, Esteves Marta, Saraiva Cláudia, Je Goun, Cortes Luísa, Valero Jorge, Alves Gilberto, Klibanov Alexander, Kim Yoon-Seong, Bernardino Liliana
Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
J Neuroinflammation. 2016 Jun 4;13(1):137. doi: 10.1186/s12974-016-0600-0.
Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival.
The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice.
We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo.
Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia-induced neuroinflammation. Importantly, our results also open promising new perspectives for the therapeutic use of H1R antagonists to treat or ameliorate neurodegenerative processes.
组胺是一种胺类物质，作为外周炎症介质和中枢神经系统中的神经递质广为人知。最近，有人提出组胺作为小胶质细胞活性的一种固有调节因子发挥作用。在此，我们旨在揭示组胺在小胶质细胞吞噬活性和活性氧（ROS）产生中的作用，并探讨组胺诱导的神经炎症对多巴胺能（DA）神经元存活的影响。
通过使用小鼠N9小胶质细胞系和原代小胶质细胞培养物在体外以及在体内评估组胺对吞噬作用的影响。细胞分别暴露于IgG调理的乳胶珠或磷脂酰丝氨酸（PS）脂质体，以分别评估Fcγ或PS受体介导的小胶质细胞吞噬作用。评估ROS产生以及NADPH氧化酶和Rac1的蛋白质水平作为氧化应激的指标。通过计数小鼠黑质（SN）中酪氨酸羟化酶阳性神经元的数量在体内评估DA神经元的存活情况。
我们发现组胺通过组胺受体1（H1R）激活触发小胶质细胞吞噬作用，并通过H1R和H4R激活产生活性氧。通过使用广谱NADPH氧化酶（Nox）抑制剂阿朴吗啡和Nox1基因敲除小鼠，我们发现Nox1信号通路参与了组胺在体外诱导的吞噬作用和ROS产生。有趣的是，阿朴吗啡和膜联蛋白V（用作PS诱导吞噬作用的抑制剂）在体内均完全消除了成年小鼠SN中注射组胺诱导的DA神经毒性。阻断H1R可在体内防止组胺诱导的Nox1表达和DA神经元死亡。
总体而言，我们的结果突出了组胺在调节小胶质细胞活性中的相关性，这最终可能在帕金森病（PD）以及最终其他伴有小胶质细胞诱导的神经炎症的神经退行性疾病中干扰神经元存活。重要的是，我们的结果还为H1R拮抗剂治疗或改善神经退行性过程的治疗应用开辟了有前景的新视角。
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