Role of the Peli1–RIPK1 Signaling Axis in Methamphetamine-Induced Neuroinflammation

作者：Weixiao Xu, Tingyu Yang, Xinyu Lou, Jingrong Chen, Xi Wang, Miaoyang Hu, Di An, Rong Gao, Jun Wang, Xufeng Chen · 发表于：ACS Chemical Neuroscience · 年份：2023 · DOI：10.1021/acschemneuro.2c00623 · 被引用次数：11 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune Response and Inflammation、interferon and immune responses

Severe neurological inflammation is one of the main symptoms of methamphetamine (meth)-induced brain injury. Studies have demonstrated that meth exposure facilitates neuroinflammation via Pellino E3 ubiquitin protein ligase 1 (Peli1)-mediated signaling. However, the involved mechanisms remain incompletely understood. Herein, we used Peli1 –/– mice and Peli1-knockdown microglial BV2 cells to decipher the roles of Peli1 and downstream signaling in meth-induced neuroinflammation. After meth administration for seven consecutive days, Peli1 –/– mice exhibited better learning and memory behavior and dramatically lower interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels than wild-type mice. Moreover, in vitro experiments revealed that Peli1 knockdown significantly attenuated the meth-induced upregulation of cytokines. Besides, meth markedly activated and increased the levels of receptor-interacting protein kinase 1 (RIPK1), and Peli1 knockout or knockdown prevented these effects, indicating that RIPK1 participated in meth-induced Peli1-mediated inflammation. Specifically, treating the cells with necrostatin-1(Nec-1), an antagonist of RIPK1, remarkably inhibited the meth-induced increase in IL-1β, TNF-α, and IL-6 expression, confirming the involvement of RIPK1 in Peli1-mediated neuroinflammation. Finally, meth induced a dramatic transfer of the mixed lineage kinase domain-like protein, a downstream effector of RIRK1, to the cell membrane, disrupting membrane integrity...