Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury

Phagocytosis of synaptic material by microglia is critical for central nervous system development. Less well understood is this microglial function in the injured adult brain. Assay of microglial phagocytosis is challenging, because peripheral myeloid cells engraft the site of injury, which could ob...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 215; no. 7; pp. 1789 - 1801
Main Authors:	Norris, Geoffrey T, Smirnov, Igor, Filiano, Anthony J, Shadowen, Hannah M, Cody, Kris R, Thompson, Jeremy A, Harris, Tajie H, Gaultier, Alban, Overall, Christopher C, Kipnis, Jonathan
Format:	Journal Article
Language:	English
Published:	United States Rockefeller University Press 02-07-2018
Subjects:	Animals Brain CD11b antigen CD11b Antigen - metabolism Cell Proliferation Central nervous system Central Nervous System - immunology Central Nervous System - injuries Central Nervous System - pathology Complement activation Complement component C1q Complement System Proteins - metabolism Debris Degeneration Detritus Gene Expression Profiling Gene sequencing Geniculate Bodies - pathology Injuries Lateral geniculate nucleus Mice, Inbred C57BL Microglia Microglia - metabolism Microglia - pathology Myeloid cells Nerve Crush Nerve Degeneration - pathology Neurodegeneration Neurons - metabolism Neurons - pathology Nuclei Optic nerve Optic Nerve - pathology Phagocytes Phagocytosis Pharmacology Ribonucleic acid RNA Synapses Synapses - metabolism Synapses - pathology
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Summary:	Phagocytosis of synaptic material by microglia is critical for central nervous system development. Less well understood is this microglial function in the injured adult brain. Assay of microglial phagocytosis is challenging, because peripheral myeloid cells engraft the site of injury, which could obscure interpretation of microglial roles. The model used here, optic nerve crush injury, results in degeneration of synapses in the dorsal lateral geniculate nucleus (dLGN), which stimulates rapid activation and engulfment of synaptic material by resident microglia without myeloid cell engraftment. Pharmacological depletion of microglia causes postinjury accumulation of synaptic debris, suggesting that microglia are the dominant postinjury phagocytes. Genetic or pharmacological manipulations revealed that neuronal activity does not trigger microglia phagocytosis after injury. RNA sequencing reveals C1q and CD11b/CR3 involvement in clearance of debris by dLGN-resident microglia. Indeed, and mice exhibit impaired postinjury debris clearance. Our results show how neurodegenerative debris is cleared by microglia and offers a model for studying its mechanisms and physiological roles.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 A.J. Filiano’s present address is Dept. of Neurosurgery, Duke University, Durham, NC. G.T. Norris's present address is Dept. of Immunology, University of Washington, Seattle, WA.
ISSN:	0022-1007 1540-9538
DOI:	10.1084/jem.20172244