TY - JOUR
T1 - Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury
AU - Norris, Geoffrey T.
AU - Smirnov, Igor
AU - Filiano, Anthony J.
AU - Shadowen, Hannah M.
AU - Cody, Kris R.
AU - Thompson, Jeremy A.
AU - Harris, Tajie H.
AU - Gaultier, Alban
AU - Overall, Christopher C.
AU - Kipnis, Jonathan
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (MH096484 and NS096967) to J. Kipnis. Authors declare no competing financial interests.
Publisher Copyright:
© 2018 Norris et al.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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, C1qa−/− and Itgam−/− 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.
AB - 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, C1qa−/− and Itgam−/− 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.
UR - http://www.scopus.com/inward/record.url?scp=85054658945&partnerID=8YFLogxK
U2 - 10.1084/jem.20172244
DO - 10.1084/jem.20172244
M3 - Article
C2 - 29941548
AN - SCOPUS:85054658945
SN - 0022-1007
VL - 215
SP - 1789
EP - 1801
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -