Abstract
Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our understanding of the cross talk between the ischemic brain and the immune system is limited. Recently, we demonstrated that following focal ischemia, death of mature viable neurons can be executed through phagocytosis by microglial cells or recruited macrophages, i.e. through phagoptosis. It was shown that inhibition of phagocytic signaling pathways following endothelin-1 induced focal cerebral ischemia leads to increased neuronal survival and neurological recovery. This suggests that inhibition of specific phagocytic pathways may prevent neuronal death during cerebral ischemia. To further explore this potential therapeutic target, we propose to assess the role of phagocytosis in an established model of temporary (45min) middle cerebral artery occlusion (tMCAo), and to evaluate neuronal survival and neurological recovery in mice with deficient phagocytosis. The primary outcome of this study will be forelimb function assessed with the staircase test. Secondary outcomes constitute Rotarod performance, stroke volume (quantified on MR imaging or brain sections, respectively), diffusion tensor imaging (DTI) connectome mapping, and histological analyses to measure neuronal and microglial densities, and phagocytic activity. Male mice aged 10-12 weeks will be used for experiments.
Highlights
Stroke is the second leading cause of death and a major cause of disability worldwide
Microglial phagocytosis is closely controlled by the expression of specific cell surface ligands
MFG-E8, a glycoprotein produced by microglia and astrocytes during inflammation, simultaneously engages exposed PS and the microglial vitronectin receptor, thereby activating phagocytosis[12,13]
Summary
Forelimb function assessed with the staircase test. Secondary outcomes constitute Rotarod performance, stroke volume (quantified on MR imaging or brain sections, respectively), diffusion tensor imaging (DTI) connectome mapping, and histological analyses to measure neuronal and microglial densities, and phagocytic activity. One of the main effector functions of microglia is the phagocytic removal of cell debris or dying cells In these cases phagocytosis is beneficial, because it prevents the disintegration of apoptotic cells and induces an anti-inflammatory response in microglia, thereby contributing to tissue homeostasis and repair (for review see Brown & Neher, 2014)[4]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.