De Luca Ciro, Colangelo Anna Maria, Alberghina Lilia, Papa Michele
Laboratory of Morphology of Neuronal Network, Department of Public Medicine, University of Campania-Luigi Vanvitelli, Naples, Italy.
Laboratory of Neuroscience "R. Levi-Montalcini", Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
Front Cell Neurosci. 2018 Nov 26;12:459. doi: 10.3389/fncel.2018.00459. eCollection 2018.
Coagulation and the immune system interact in several physiological and pathological conditions, including tissue repair, host defense, and homeostatic maintenance. This network plays a key role in diseases of the central nervous system (CNS) by involving several cells (CNS resident cells, platelets, endothelium, and leukocytes) and molecular pathways (protease activity, complement factors, platelet granule content). Endothelial damage prompts platelet activation and the coagulation cascade as the first physiological step to support the rescue of damaged tissues, a flawed rescuing system ultimately producing neuroinflammation. Leukocytes, platelets, and endothelial cells are sensitive to the damage and indeed can release or respond to chemokines and cytokines (platelet factor 4, CXCL4, TNF, interleukins), and growth factors (including platelet-derived growth factor, vascular endothelial growth factor, and brain-derived neurotrophic factor) with platelet activation, change in capillary permeability, migration or differentiation of leukocytes. Thrombin, plasmin, activated complement factors and matrix metalloproteinase-1 (MMP-1), furthermore, activate intracellular transduction through complement or protease-activated receptors. Impairment of the neuro-immune hemostasis network induces acute or chronic CNS pathologies related to the neurovascular unit, either directly or by the systemic activation of its main steps. Neurons, glial cells (astrocytes and microglia) and the extracellular matrix play a crucial function in a "tetrapartite" synaptic model. Taking into account the neurovascular unit, in this review we thoroughly analyzed the influence of neuro-immune hemostasis on these five elements acting as a functional unit ("pentapartite" synapse) in the adaptive and maladaptive plasticity and discuss the relevance of these events in inflammatory, cerebrovascular, Alzheimer, neoplastic and psychiatric diseases. Finally, based on the solid reviewed data, we hypothesize a model of neuro-immune hemostatic network based on protein-protein interactions. In addition, we propose that, to better understand and favor the maintenance of adaptive plasticity, it would be useful to construct predictive molecular models, able to enlighten the regulating logic of the complex molecular network, which belongs to different cellular domains. A modeling approach would help to define how nodes of the network interact with basic cellular functions, such as mitochondrial metabolism, autophagy or apoptosis. It is expected that dynamic systems biology models might help to elucidate the fine structure of molecular events generated by blood coagulation and neuro-immune responses in several CNS diseases, thereby opening the way to more effective treatments.
凝血与免疫系统在多种生理和病理状况下相互作用，包括组织修复、宿主防御和内环境稳态维持。该网络通过涉及多种细胞（中枢神经系统驻留细胞、血小板、内皮细胞和白细胞）和分子途径（蛋白酶活性、补体因子、血小板颗粒内容物）在中枢神经系统（CNS）疾病中发挥关键作用。内皮损伤促使血小板活化和凝血级联反应，作为支持受损组织修复的首个生理步骤，而有缺陷的修复系统最终会引发神经炎症。白细胞、血小板和内皮细胞对损伤敏感，并且在血小板活化、毛细血管通透性改变、白细胞迁移或分化时，确实能够释放或响应趋化因子和细胞因子（血小板因子4、CXCL4、肿瘤坏死因子、白细胞介素）以及生长因子（包括血小板衍生生长因子、血管内皮生长因子和脑源性神经营养因子）。此外，凝血酶、纤溶酶、活化的补体因子和基质金属蛋白酶 -1（MMP -1）通过补体或蛋白酶激活受体激活细胞内转导。神经免疫止血网络的损伤直接或通过其主要步骤的全身激活，诱发与神经血管单元相关的急性或慢性中枢神经系统病理状况。神经元、神经胶质细胞（星形胶质细胞和小胶质细胞）和细胞外基质在“四联”突触模型中发挥关键作用。考虑到神经血管单元，在本综述中，我们全面分析了神经免疫止血对这五个作为功能单元（“五联”突触）发挥作用的要素在适应性和适应不良可塑性方面的影响，并讨论了这些事件在炎症性、脑血管性、阿尔茨海默病、肿瘤性和精神性疾病中的相关性。最后，基于充分的综述数据，我们假设了一个基于蛋白质 - 蛋白质相互作用的神经免疫止血网络模型。此外，我们提出，为了更好地理解和促进适应性可塑性的维持，构建能够阐明属于不同细胞结构域的复杂分子网络调节逻辑的预测性分子模型将是有用的。一种建模方法将有助于确定网络节点如何与基本细胞功能相互作用，如线粒体代谢、自噬或凋亡。预计动态系统生物学模型可能有助于阐明几种中枢神经系统疾病中由血液凝固和神经免疫反应产生的分子事件的精细结构，从而为更有效的治疗开辟道路。
