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- W2980907031 abstract "RIP Kinase 1 (RIPK1) activates necroptotic cell death in response to pro-inflammatory signaling in cells where apoptotic signaling has been compromised. RIPK1 kinase activity has been implicated in Alzheimer's disease progression, presumably by triggering the formation of the necrosome with RIPK3 and MLKL. Based on these data, clinical trials of RIPK1 inhibitors in AD have been initiated. We investigated the role of RIPK1 in microglial activation by analyzing RIPK1 signaling in vitro and in vivo. To identify RIPK1 dependent signaling pathways, we activated BV2 microglia-like cells with 9 different pro-inflammatory stimuli plus/minus RIPK1 inhibitors and performed RNAseq followed by pathway analysis. To understand the role of RIPK1 in neurodegeneration, we dosed CDK5/p25 and 5XFAD mice with highly selective RIPK1 inhibitors before examining cytokine levels and transcriptional changes in microglia. In wild type, p25, Tg4510, and 5xFAD mice, RIPK1 is expressed predominantly in microglia, while MLKL expression is absent or very low; furthermore the characteristic phosphorylation of RIPK1 and RIPK3 that occurs upon necrosome formation was not detectable in these models even when cell death is occurring. These data suggests RIPK1 signals through a novel mechanism in microglia. BV2 cells, which unlike native mouse microglia express both RIPK3 and MLKL, can undergo RIPK1-depedent necroptosis. However these cells also responded in a RIPK1-dependent manner to diverse pro-inflammatory stimuli, with RIPK1 apparently promoting IRF8/Pu.1, NF-kB, and NRLP3 inflammasome pathways without triggering necrosome formation. Sub-chronic treatment of 5xFAD and CDK5/p25 mice with RIPK1 inhibitor partially normalizes cytokine levels and alters the expression of a subset of key microglial genes. Here we comprehensively map the function of RIPK1 in a microglia-like cell line across a range of inflammatory stimuli and conclude that RIPK1 signaling promotes an inflammatory response that involves modulation of key regulatory pathways but not the induction of the necrosome." @default.
- W2980907031 created "2019-10-25" @default.
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- W2980907031 date "2019-07-01" @default.
- W2980907031 modified "2023-10-16" @default.
- W2980907031 title "P4‐690: RIP KINASE 1 (RIPK1) MODULATES SELECTIVE PATHWAYS UNDERLYING THE MICROGLIAL RESPONSE TO A BROAD RANGE OF INFLAMMATORY AND NEURODEGENERATIVE STIMULI WITHOUT ELICITING NECROPTOSIS" @default.
- W2980907031 doi "https://doi.org/10.1016/j.jalz.2019.09.055" @default.
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