Changhong Xing1, Xiaoshu Wang2, Chongjie Cheng2, Joan Montaner2, Emiri Mandeville2, Wendy Leung2, Klaus van Leyen2, Josephine Lok2, Xiaoying Wang2, Eng H Lo1. 1. From the Departments of Radiology, Neurology, and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown (C.X., Xiaoshu Wang, C.C., E.M., W.L., K.v.L., J.L., Xiaoying Wang, E.H.L.); Department of Neurosurgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, China (Xiaoshu Wang, C.C.); and Neurovascular Research Laboratory, Vall d'Hebron University Hospital Research Institute, Barcelona, Spain (J.M.). Lo@helix.mgh.harvard.edu xing.changhong@mgh.harvard.edu. 2. From the Departments of Radiology, Neurology, and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Charlestown (C.X., Xiaoshu Wang, C.C., E.M., W.L., K.v.L., J.L., Xiaoying Wang, E.H.L.); Department of Neurosurgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, China (Xiaoshu Wang, C.C.); and Neurovascular Research Laboratory, Vall d'Hebron University Hospital Research Institute, Barcelona, Spain (J.M.).
Abstract
BACKGROUND AND PURPOSE: We explored the hypothesis that injured neurons release lipocalin-2 as a help me signal. METHODS: In vivo lipocalin-2 responses were assessed in rat focal cerebral ischemia and human stroke brain samples using a combination of ELISA and immunostaining. In vitro, microglia and astrocytes were exposed to lipocalin-2, and various markers and assays of glial activation were quantified. Functional relevance of neuron-to-glia lipocalin-2 signaling was examined by transferring conditioned media from lipocalin-2-activated microglia and astrocytes onto neurons to see whether activated glia could protect neurons against oxygen-glucose deprivation and promote neuroplasticity. RESULTS: In human stroke samples and rat cerebral ischemia, neuronal expression of lipocalin-2 was significantly increased. In primary cell cultures, exposing microglia and astrocytes to lipocalin-2 resulted in glial activation. In microglia, lipocalin-2 converted resting ramified shapes into a long-rod morphology with reduced branching, increased interleukin-10 release, and enhanced phagocytosis. In astrocytes, lipocalin-2 upregulated glial fibrillary acid protein, brain-derived neurotropic factor, and thrombospondin-1. Conditioned media from lipocalin-2-treated astrocytes upregulated synaptotagmin, and conditioned media from lipocalin-2-treated microglia upregulated synaptophysin and post-synaptic density 95 (PSD95) and protected neurons against oxygen-glucose deprivation. CONCLUSIONS: These findings provide proof of concept that lipocalin-2 is released by injured neurons as a help me distress signal that activates microglia and astrocytes into potentially prorecovery phenotypes.
RCT Entities:
BACKGROUND AND PURPOSE: We explored the hypothesis that injured neurons release lipocalin-2 as a help me signal. METHODS: In vivo lipocalin-2 responses were assessed in ratfocal cerebral ischemia and humanstroke brain samples using a combination of ELISA and immunostaining. In vitro, microglia and astrocytes were exposed to lipocalin-2, and various markers and assays of glial activation were quantified. Functional relevance of neuron-to-glia lipocalin-2 signaling was examined by transferring conditioned media from lipocalin-2-activated microglia and astrocytes onto neurons to see whether activated glia could protect neurons against oxygen-glucose deprivation and promote neuroplasticity. RESULTS: In humanstroke samples and ratcerebral ischemia, neuronal expression of lipocalin-2 was significantly increased. In primary cell cultures, exposing microglia and astrocytes to lipocalin-2 resulted in glial activation. In microglia, lipocalin-2 converted resting ramified shapes into a long-rod morphology with reduced branching, increased interleukin-10 release, and enhanced phagocytosis. In astrocytes, lipocalin-2 upregulated glial fibrillary acid protein, brain-derived neurotropic factor, and thrombospondin-1. Conditioned media from lipocalin-2-treated astrocytes upregulated synaptotagmin, and conditioned media from lipocalin-2-treated microglia upregulated synaptophysin and post-synaptic density 95 (PSD95) and protected neurons against oxygen-glucose deprivation. CONCLUSIONS: These findings provide proof of concept that lipocalin-2 is released by injured neurons as a help me distress signal that activates microglia and astrocytes into potentially prorecovery phenotypes.
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