NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration.

Ruijia Liu, Jun Wang, Yang Chen, Jenelle M Collier, Okan Capuk, Shijie Jin, Ming Sun, Sujan K Mondal, Theresa L Whiteside, Donna B Stolz, Yongjie Yang, Gulnaz Begum

Cell death & disease 2022 Apr 19

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Reactive astrocytes (RA) secrete lipocalin-2 (LCN2) glycoprotein that regulates diverse cellular processes including cell death/survival, inflammation, iron delivery and cell differentiation. Elevated levels of LCN2 are considered as a biomarker of brain injury, however, the underlying regulatory mechanisms of its expression and release are not well understood. In this study, we investigated the role of astrocytic Na+/H+ exchanger 1 (NHE1) in regulating reactive astrocyte LCN2 secretion and neurodegeneration after stroke. Astrocyte specific deletion of Nhe1 in Gfap-CreER+/-;Nhe1f/f mice reduced astrogliosis and astrocytic LCN2 and GFAP expression, which was associated with reduced loss of NeuN+ and GRP78+ neurons in stroke brains. In vitro ischemia in astrocyte cultures triggered a significant increase of secreted LCN2 in astrocytic exosomes, which caused neuronal cell death and neurodegeneration. Inhibition of NHE1 activity during in vitro ischemia with its potent inhibitor HOE642 significantly reduced astrocytic LCN2+ exosome secretion. In elucidating the cellular mechanisms, we found that stroke triggered activation of NADPH oxidase (NOX)-NF-κB signaling and ROS-mediated LCN2 expression. Inhibition of astrocytic NHE1 activity attenuated NOX signaling and LCN2-mediated neuronal apoptosis and neurite degeneration. Our findings demonstrate for the first time that RA use NOX signaling to stimulate LCN2 expression and secretion. Blocking astrocytic NHE1 activity is beneficial to reduce LCN2-mediated neurotoxicity after stroke. © 2022. The Author(s).

Citation

Ruijia Liu, Jun Wang, Yang Chen, Jenelle M Collier, Okan Capuk, Shijie Jin, Ming Sun, Sujan K Mondal, Theresa L Whiteside, Donna B Stolz, Yongjie Yang, Gulnaz Begum. NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration. Cell death & disease. 2022 Apr 19;13(4):371