School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Int J Mol Sci. 2022 Aug 12;23(16):9041. doi: 10.3390/ijms23169041.
The accumulation of microglia around senile plaques is one of the pathological features of Alzheimer's disease (AD). Chemerin is an adipokine with immune-modulating properties. Our previous study showed that chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, is also a functional receptor of Aβ. However, it remains unclear whether and how the chemerin/CMKLR1 axis affects the migration of microglia. The impact of CMKLR1 on microglial activation and recruitment toward Aβ deposits was examined in APP/PS1 mice mated with CMKLR1 knockout () mice. CMKLR1 deficiency reduced the number of microglia around Aβ deposits in aged APP/PS1- mice compared with APP/PS1 mice. Chemerin expression was significantly decreased in the hippocampus and cortex of aged APP/PS1 mice compared with WT mice. In vitro assays demonstrated that activation of the chemerin/CMKLR1 axis promoted the migration of primary cultures of microglia and murine microglial N9 cells. Mechanistic studies found that chemerin/CMKLR1 induced polarization and protrusion formation of microglia by promoting the remodeling of actin filaments and microtubules, and Golgi apparatus reorientation. The inhibition of p38 MAPK attenuated the promotion of the chemerin/CMKLR1 axis on microglial migration and polarization. In addition, chemerin inhibited Aβ-induced microglial clustering. The inhibition of p38 MAPK alleviated the suppressive effect of chemerin on Aβ-induced microglial aggregation. Our data indicate that the chemerin/CMKLR1 axis is involved in the migration and recruitment of microglia to senile plaques via the p38 MAPK pathway. Modulation of the chemerin/CMKLR1 axis is a potential new strategy for AD therapy.
小胶质细胞在老年斑周围的积累是阿尔茨海默病（AD）的病理特征之一。趋化素样受体 1（CMKLR1）是趋化素的受体，也是 Aβ的功能性受体。然而，趋化素/CMKLR1 轴是否以及如何影响小胶质细胞的迁移仍不清楚。在与 CMKLR1 敲除（）小鼠交配的 APP/PS1 小鼠中，研究了 CMKLR1 对小胶质细胞激活和向 Aβ沉积处募集的影响。与 APP/PS1 小鼠相比，CMKLR1 缺陷减少了老年 APP/PS1-小鼠中 Aβ沉积周围的小胶质细胞数量。与 WT 小鼠相比，老年 APP/PS1 小鼠海马和皮质中的趋化素表达显著降低。体外实验表明，激活趋化素/CMKLR1 轴可促进原代培养的小胶质细胞和小鼠小胶质细胞 N9 细胞的迁移。机制研究发现，趋化素/CMKLR1 通过促进肌动蛋白丝和微管的重塑以及高尔基体重定向，诱导小胶质细胞的极化和突起形成。p38 MAPK 的抑制减弱了趋化素/CMKLR1 轴对小胶质细胞迁移和极化的促进作用。此外，趋化素抑制 Aβ诱导的小胶质细胞聚集。p38 MAPK 的抑制减轻了趋化素对 Aβ诱导的小胶质细胞聚集的抑制作用。我们的数据表明，趋化素/CMKLR1 轴通过 p38 MAPK 途径参与小胶质细胞向老年斑的迁移和募集。趋化素/CMKLR1 轴的调节可能是 AD 治疗的一种新策略。
