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RIPK1 Regulates Microglial Activation in Lipopolysaccharide-Induced Neuroinflammation and MPTP-Induced Parkinson's Disease Mouse Models
- Title
- RIPK1 Regulates Microglial Activation in Lipopolysaccharide-Induced Neuroinflammation and MPTP-Induced Parkinson's Disease Mouse Models
- Authors
- Kim, Do-Yeon; Leem, Yea-Hyun; Park, Jin-Sun; Park, Jung-Eun; Park, Jae-Min; Kang, Jihee Lee; Kim, Hee-Sun
- Ewha Authors
- 이지희; 김희선; 박진선; 임예현
- SCOPUS Author ID
- 이지희; 김희선; 박진선; 임예현
- Issue Date
- 2023
- Journal Title
- CELLS
- ISSN
- 2073-4409
- Citation
- CELLS vol. 12, no. 3
- Keywords
- RIPK1; necrostatin-1; microglial activation; neuroinflammation; necroptosis; Parkinson's disease; neuroprotection
- Publisher
- MDPI
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Increasing evidence suggests a pivotal role of receptor-interacting protein kinase 1 (RIPK1), an initiator of necroptosis, in neuroinflammation. However, the precise role of RIPK1 in microglial activation remains unclear. In the present study, we explored the role of RIPK1 in lipopolysaccharide (LPS)-induced neuroinflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice by using RIPK1-specific inhibitors necrostatin-1 (Nec-1) and necrostatin-1 stable (Nec-1s). Nec-1/Nec-1s or RIPK1 siRNA inhibited the production of proinflammatory molecules and the phosphorylation of RIPK1-RIPK3-MLKL and cell death in LPS-induced inflammatory or LPS/QVD/BV6-induced necroptotic conditions of BV2 microglial cells. Detailed mechanistic studies showed that Nec-1/Nec-1s exerted anti-inflammatory effects by modulating AMPK, PI3K/Akt, MAPKs, and NF-kappa B signaling pathways in LPS-stimulated BV2 cells. Subsequent in vivo studies showed that Nec-1/Nec-1s inhibited microglial activation and proinflammatory gene expression by inhibiting the RIPK1 phosphorylation in the brains of LPS-injected mice. Furthermore, Nec-1/Nec-1s exert neuroprotective and anti-inflammatory effects in MPTP-induced PD mice. We found that p-RIPK1 is mainly expressed in microglia, and thus RIPK1 may contribute to neuroinflammation and subsequent cell death of dopaminergic neurons in MPTP-induced PD model mice. These data suggest that RIPK1 is a key regulator of microglial activation in LPS-induced neuroinflammation and MPTP-induced PD mice.
- DOI
- 10.3390/cells12030417
- Appears in Collections:
- 의과대학 > 의학과 > Journal papers
- Files in This Item:
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cells-12-00417-v2.pdf(4.62 MB)
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