Briens Aurélien, Bardou Isabelle, Lebas Héloïse, Miles Lindsey A, Parmer Robert J, Vivien Denis, Docagne Fabian
INSERM/University of Caen Normandie, INSERM U1237, GIP Cyceron, Physiopathology and Imaging of Neurological Disorders (PhIND), Caen, France.
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA.
Cell Discov. 2017 Feb 21;3:17001. doi: 10.1038/celldisc.2017.1. eCollection 2017.
Plasminogen activation is involved in many processes within the central nervous system, including synaptic plasticity, neuroinflammation and neurodegeneration. However, the mechanisms that regulate plasminogen activation in the brain still remain unknown. Here we demonstrate that astrocytes participate in this regulation by two mechanisms. First, the astrocyte plasma membrane serves as a surface for plasminogen activation by tissue-type plasminogen activator. This activation triggers downstream plasmin-dependent processes with important impacts in brain health and disease, such as fibrinolysis and brain-derived neurotrophic factor conversion. Second, astrocytes take up plasminogen and plasmin in a regulated manner through a novel mechanism involving endocytosis mediated by cell-surface actin and triggered by extracellular plasmin activity at the surface of astrocytes. Following endocytosis, plasminogen and plasmin are targeted to lysosomes for degradation. Thus, cell-surface actin acts as a sensor of plasmin activity to induce a negative feedback through plasmin endocytosis. This study provides evidence that astrocytes control the balance between plasmin formation and plasmin elimination in the brain parenchyma.
纤溶酶原激活参与中枢神经系统内的许多过程，包括突触可塑性、神经炎症和神经退行性变。然而，调节脑内纤溶酶原激活的机制仍不清楚。在此，我们证明星形胶质细胞通过两种机制参与这种调节。首先，星形胶质细胞质膜作为组织型纤溶酶原激活物激活纤溶酶原的表面。这种激活触发下游纤溶酶依赖性过程，对脑健康和疾病有重要影响，如纤维蛋白溶解和脑源性神经营养因子转化。其次，星形胶质细胞通过一种新机制以受调控的方式摄取纤溶酶原和纤溶酶，该机制涉及由细胞表面肌动蛋白介导的内吞作用，并由星形胶质细胞表面的细胞外纤溶酶活性触发。内吞作用后，纤溶酶原和纤溶酶靶向溶酶体进行降解。因此，细胞表面肌动蛋白作为纤溶酶活性的传感器，通过纤溶酶内吞作用诱导负反馈。这项研究提供了证据，表明星形胶质细胞控制脑实质中纤溶酶形成与纤溶酶清除之间的平衡。
