After cerebral ischemia or trauma, microglia are initially activated into a damaging inflammatory phenotype. But eventually, they may switch to a beneficial pro-remodeling phenotype as the brain tries to recover. This project dissects a novel mechanism that allows cerebral endothelium and reactive astrocytes todifferentially regulate the microglial switch. Our hypothesis is as follows. Normally, brain microglia cannot "see" cerebral endothelium because they reside behind the BBB. During acute injury, the BBB is leaky and microglia now "see" microparticles that are released by damaged or inflammed cerebral endothelium. This activates them into a deleterious phenotype (e.g. high TNF? and IL1?). After this initial injury stage subsides, the blood-brain barrier (BBB) is repaired and reactive astrocytes emerge that begin to release pro-recovery mediators such as high-mobility-groupbox-1 (HMGB1), IL-4 and IL-10. This causes microglia to switch to a beneficial phenotype (e.g. high growth factors). Our project will dissect the inter- and intra-cellular mechanisms involved in this gliovascular regulation of the microglial switch.
In Aim 1, we use cell cultures to show that conditioned media from endothelium vs astrocytes have opposite effects on microglia activation. Then we show that harmful vs beneficial microglia have either neurotoxic or neuroplastic effects when added to primary neurons.
In Aim 2, we will confirm that the differential effects of endothelium vs astrocytes is mediated by release of microparticles, HMGB1, IL-4 and IL-10.
In Aim 3, we will correlate the temporal profiles of BBB leakage, astrocytosis and biphasic microglia after focal cerebral ischemia or trauma in mice. We will also directly inject endothelial microparticles oractivate astrocytes via optogenetics to see whether we can evoke the predicted microglial phenotypes in vivo. Synergizing with Project 2, we will try to asses these microglial pathways in white matter as well. And synergizing with Project 3, we will try to manipulate rho-kinase pathways to switch microglia into a beneficial mode and promote recovery. Imaging and optogenetics will be supported by Core A. Neurorecovery in our mouse models will be supported by Core B. Taken together, our studies should define a mechanism by which endothelium and astrocytes regulate the microglial switch in the remodeling neurovascular unit. These findings may eventually lead to therapeutic opportunities for promoting repair and recovery after stroke and neurodegeneration.

Public Health Relevance

Microglia play a key role in neurorecovery after stroke and bran trauma. By understanding the mechanisms that govern their good vs bad phenotypes, we may be able to better design therapies to promote clinical recovery in stroke patients.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
2P01NS055104-06A1
Application #
8662868
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Bosetti, Francesca
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Shindo, Akihiro; Maki, Takakuni; Mandeville, Emiri T et al. (2016) Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke. Stroke 47:1094-100
Chung, David Y; Oka, Fumiaki; Ayata, Cenk (2016) Spreading Depolarizations: A Therapeutic Target Against Delayed Cerebral Ischemia After Subarachnoid Hemorrhage. J Clin Neurophysiol 33:196-202
Liang, Anna C; Mandeville, Emiri T; Maki, Takakuni et al. (2016) Effects of Aging on Neural Stem/Progenitor Cells and Oligodendrocyte Precursor Cells After Focal Cerebral Ischemia in Spontaneously Hypertensive Rats. Cell Transplant 25:705-14
Seidel, Jessica L; Escartin, Carole; Ayata, Cenk et al. (2016) Multifaceted roles for astrocytes in spreading depolarization: A target for limiting spreading depolarization in acute brain injury? Glia 64:5-20
Wu, Limin; Ramirez, Servio H; Andrews, Allison M et al. (2016) Neuregulin1-β decreases interleukin-1β-induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability. J Neurochem 136:250-7
Xing, Changhong; Lo, Eng H (2016) Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery. Prog Neurobiol :
Mandeville, Emiri T; Ayata, Cenk; Zheng, Yi et al. (2016) Translational MR Neuroimaging of Stroke and Recovery. Transl Stroke Res :
Egawa, Naohiro; Lok, Josephine; Washida, Kazuo et al. (2016) Mechanisms of Axonal Damage and Repair after Central Nervous System Injury. Transl Stroke Res :
Arai, Ken (2016) Stroke Literature Synopses: Basic Science. Stroke 47:e250-e251
Arai, Ken (2016) Stroke Literature Synopses: Basic Science. Stroke 47:e40-1

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