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Ripks and Neuroinflammation

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Abstract

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson’s disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

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This work was funded by the National Natural Science Funds of China (Grant Nos. 81971098 and 82104144).

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  1. Yue Xu and Feng Lin contributed equally to this work

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  1. Department of Cerebrovascular Disease, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People’s Republic of China

    Yue Xu, Feng Lin, Guolei Liao, Jiaxing Sun & Lei Zhang

  2. Department of Pharmacy, Sun Yat-Sen University, The Fifth Affiliated Hospital, Zhuhai, 519000, Guangdong, People’s Republic of China

    Wenli Chen

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All authors contributed to the study conception and design. CW and ZL: conceptualization. XY and LF: writing original draft preparation. LG and SJ: reviewing and editing. XY and LF: contribute equally to this manuscript.

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Xu, Y., Lin, F., Liao, G. et al. Ripks and Neuroinflammation. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03981-4

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