Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death

Brain infection, trauma, ischemia, aging and neurodegeneration are accompanied by in-flammation, which can exert both pro-survival and pro-death effects. Dead and dying neurons are quickly removed through phagocytosis by microglia. Therefore, it has been assumed that phagocytosis of neurons during inflammation is also secondary to neuronal necrosis or apoptosis. However, we report here that under inflammatory conditions in co-cultures of neurons and glia, phagocytosis actively contributes to neuronal death. Two inflammatory bacterial ligands, lipoteichoic acid or lipopolysaccharide (agonists of glial Toll-like receptors-2 & -4 respectively) stimulated microglial phagocytosis and peroxyni-trite release. Peroxynitrite levels, however, were insufficient to directly cause neuronal death; rather, they resulted in transient neuronal eat-me signal exposure followed by en-gulfment and death of 20-40% of neurons after 3 days. Conversely, blocking any step in a phagocytic signaling pathway consisting of phosphatidylserine (PS) exposure, the PS-binding bridging protein Milk fat globule EGF factor-8 and its microglial vitronectin re-ceptor rescued up to 90% of the neurons without reducing inflammation. Importantly, these protected neurons survived and appeared identical to untreated neurons. Hence, peroxynitrite released by inflammatory-activated microglia can cause eat-me signal expo-sure by otherwise viable neurons leading to their death by phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration.

NEHER Jonas J;  NENISKYTE Urte;  ZHAO Jing-Wei;  PRICE Anna;  TOLKOVSKY Aviva M.;  BROWN Guy C.; 

2011-12-16

AMER ASSOC IMMUNOLOGISTS

JRC60283

0022-1767,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC60283,   

10.4049/jimmunol.1003600,