Antagonism of β-arrestins in IL-4–driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson’s disease

作者：Jiaqi Liu, Yue Liang, Qing‐Hao Meng, Jiayu Chen, Junwei Ma, Hong Zhu, Lei Cai, Nanshan Song, Jianhua Ding, Yi Fan, Ming Lu, Guangyu Wu, Yinquan Fang, Gang Hu · 发表于：Science Advances · 年份：2024 · DOI：10.1126/sciadv.adn4845 · 被引用次数：29 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Adenosine and Purinergic Signaling、Receptor Mechanisms and Signaling

Interleukin-4 (IL-4)-exposed microglia acquire neuroprotective properties, but their functions and regulation in Parkinson's disease (PD) are poorly understood. In this study, we demonstrate that IL-4 enhances anti-inflammatory microglia reactivity, ameliorates the pathological features of PD, and reciprocally affects expression of β-arrestin 1 and β-arrestin 2 in microglia in PD mouse models. We also show that manipulation of two β-arrestins produces contrary effects on the anti-inflammatory states and neuroprotective action of microglia induced by IL-4 in vivo and in vitro. We further find that the functional antagonism of two β-arrestins is mediated through sequential activation of sterile alpha motif domain containing 4 (Samd4), mammalian target of rapamycin (mTOR), and mitochondrial oxidative phosphorylation (OXPHOS). Collectively, these data reveal opposing functions of two closely related β-arrestins in regulating the IL-4-induced microglia reactivity via the Samd4/mTOR/OXPHOS axis in PD mouse models and provide important insights into the pathogenesis and therapeutics of PD.