Journal
CEREBRAL CORTEX
Volume 28, Issue 7, Pages 2622-2635Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhy089
Keywords
cerebral ischemia; microglia/macrophage; necroptosis; polarization
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Funding
- National Natural Science Foundation of China [81730035, 81571224]
- Ministry of Science and Technology [2014RA4029]
- Natural Science Basic Research Plan in Shaanxi Province of China [2017JM8061]
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Cell death and subsequent inflammation are 2 key pathological changes occurring in cerebral ischemia. Active microglia/macrophages play a double-edged role depending on the balance of their M1/M2 phenotypes. Necrosis is the predominant type of cell death following ischemia. However, how necrotic cells modulate the M1/M2 polarization of microglia/macrophages remains poorly investigated. Here, we reported that ischemia induces a rapid RIPK3/MLKL-mediated neuron-dominated necroptosis, a type of programmed necrosis. Ablating RIPK3 or MLKL could switch the activation of microglia/macrophages from M1 to the M2 type in the ischemic cortex. Conditioned medium of oxygen-glucose deprivation (OGD)-treated wild-type (WT) neurons induced M1 polarization, while that of RIPK3-/-neurons favored M2 polarization. OGD treatment induces proinflammatory IL-18 and TNF alpha in WT but not in RIPK3-/-neurons, which in turn upregulate anti-inflammatory IL-4 and IL-10. Furthermore, the expression of Myd88-a common downstream adaptor of toll-like receptors-is significantly upregulated in the microglia/macrophages of ischemic WT but not of RIPK3(-/-) or MLKL-/- cortices. Antagonizing the function of Myd88 could phenocopy the effects of RIPK3/MLKL-knockout on the polarization of microglia/macrophages and was neuroprotective. Our data revealed a novel role of
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