title: Microglial repopulation resolves inflammation and promotes brain recovery after injury.
abstract: Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use. Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS, affording an opportunity to renew this cellular compartment. To that end, we have explored the effects of acute microglial elimination, followed by microglial repopulation, in a mouse model of extensive neuronal loss. Neuronal loss leads to a prolonged neuroinflammatory response, characterized by the presence of swollen microglia expressing CD68 and CD45, as well as elevated levels of cytokines, chemokines, complement, and other inflammatory signals. These collective responses are largely resolved by microglial repopulation. Furthermore, microglial repopulation promotes functional recovery in mice, with elevated plus maze performance matching that of uninjured mice, despite the loss of 80% of hippocampal neurons. Analyses of synaptic surrogates revealed increases in PSD95 and synaptophysin puncta with microglial repopulation, suggesting that these cells sculpt and regulate the synaptic landscape. Thus, our results show that short-term microglial elimination followed by repopulation may represent a clinically feasible and novel approach to resolve neuroinflammatory events and promote brain recovery.
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, 92697.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Rice
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, 92697.
authors.forename: Jason
authors.initials: J
authors.lastname: Pham
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, 92697.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, 92697.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Najafi
authors.affiliation: Plexxikon Inc, Berkeley, California, 94710.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, 92697.
authors.forename: Kim N
authors.identifier: 0000-0002-6049-6744
authors.initials: KN
authors.lastname: Green
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death; D049109:Cell Proliferation / Q000502:physiology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D020127:Recovery of Function / Q000502:physiology*; D013569:Synapses / Q000473:pathology / Q000502:physiology
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins
keywords: colony-stimulating factor 1 receptor; dendritic spines; glia; neuroinflammation; neuronal loss