期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 43, 页码 E4098-E4107出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1308679110
关键词
phagoptosis; neuroinflammation
资金
- Wellcome Trust, United Kingdom [RG50995]
- Roman Herzog Postdoctoral Fellowship of the Hertie Foundation (Frankfurt, Germany)
Delayed neuronal loss and brain atrophy after cerebral ischemia contribute to stroke and dementia pathology, but the mechanisms are poorly understood. Phagocytic removal of neurons is generally assumed to be beneficial and to occur only after neuronal death. However, we report herein that inhibition of phagocytosis can prevent delayed loss and death of functional neurons after transient brain ischemia. Two phagocytic proteins, Mer receptor tyrosine kinase (MerTK) and Milk fat globule EGF-like factor 8 (MFG-E8), were transiently up-regulated by macrophages/microglia after focal brain ischemia in vivo. Strikingly, deficiency in either protein completely prevented long-term functional motor deficits after cerebral ischemia and strongly reduced brain atrophy as a result of inhibiting phagocytosis of neurons. Correspondingly, in vitro glutamate-stressed neurons reversibly exposed the eat-me signal phosphatidylserine, leading to their phagocytosis by microglia; this neuronal loss was prevented in the absence of microglia and reduced if microglia were genetically deficient in MerTK or MFG-E8, both of which mediate phosphatidylserine-recognition. Thus, phagocytosis of viable neurons contributes to brain pathology and, surprisingly, blocking this process is strongly beneficial. Therefore, inhibition of specific phagocytic pathways may present therapeutic targets for preventing delayed neuronal loss after transient cerebral ischemia.
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