Oh Yebin, Jung Hak-Jun, Hong Seungwon, Cho Yerim, Park Jiyeong, Cho Daeho, Kim Tae Sung
Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South Korea.
Institute of Convergence Science, Korea University, Seoul, South Korea.
Front Cell Neurosci. 2022 Sep 7;16:977205. doi: 10.3389/fncel.2022.977205. eCollection 2022.
Activation of microglia, which is the primary immune cell of the central nervous system, plays an important role in neuroinflammation associated with several neuronal diseases. Aminoacyl tRNA synthetase (ARS) complex-interacting multifunctional protein 1 (AIMP1), a structural component of the multienzyme ARS complex, is secreted to trigger a pro-inflammatory function and has been associated with several inflammatory diseases. However, the effect of AIMP1 on microglial activation remains unknown. AIMP1 elevated the expression levels of activation-related cell surface markers and pro-inflammatory cytokines in primary and BV-2 microglial cells. In addition to the AIMP1-mediated increase in the expression levels of M1 markers [interleukin (IL)-6, tumor necrosis factor-α, and IL-1β], the expression levels of CD68, an M1 cell surface molecule, were also increased in AIMP-1-treated microglial cells, while those of CD206, an M2 cell surface molecule, were not, indicating that AIMP1 triggers the polarization of microglial cells into the M1 state but not the M2 state. AIMP1 treatment induced the phosphorylation of mitogen-activated protein kinases (MAPKs), while MAPK inhibitors suppressed the AIMP1-induced microglial cell activation. AIMP1 also induced the phosphorylation of the nuclear factor-kappa B (NF-κB) components and nuclear translocation of the NF-κB p65 subunit in microglial cells. Furthermore, c-Jun N-terminal kinase (JNK) and p38 inhibitors markedly suppressed the AIMP1-induced phosphorylation of NF-κB components as well as the nuclear translocation of NF-κB p65 subunit, suggesting the involvement of JNK and p38 as upstream regulators of NF-κB in AIMP1-induced microglial cell activation. The NF-κB inhibitor suppressed the AIMP1-induced M1 polarization of the microglial cells. Taken together, AIMP1 effectively induces M1 microglial activation the JNK and p38/NF-κB-dependent pathways. These results suggest that AIMP1 released under stress conditions may be a pathological factor that induces neuroinflammation.
小胶质细胞是中枢神经系统的主要免疫细胞，其激活在与多种神经疾病相关的神经炎症中起重要作用。氨酰tRNA合成酶（ARS）复合物相互作用多功能蛋白1（AIMP1）是多酶ARS复合物的结构成分，可分泌以触发促炎功能，并与多种炎症性疾病相关。然而，AIMP1对小胶质细胞激活的影响尚不清楚。AIMP1提高了原代和BV-2小胶质细胞中激活相关细胞表面标志物和促炎细胞因子的表达水平。除了AIMP1介导的M1标志物[白细胞介素（IL）-6、肿瘤坏死因子-α和IL-1β]表达水平增加外，AIMP-1处理的小胶质细胞中M1细胞表面分子CD68的表达水平也增加，而M2细胞表面分子CD206的表达水平未增加，表明AIMP1触发小胶质细胞向M1状态而非M2状态极化。AIMP1处理诱导丝裂原活化蛋白激酶（MAPK）磷酸化，而MAPK抑制剂抑制AIMP1诱导的小胶质细胞激活。AIMP1还诱导小胶质细胞中核因子-κB（NF-κB）成分的磷酸化和NF-κB p65亚基的核转位。此外，c-Jun氨基末端激酶（JNK）和p38抑制剂显著抑制AIMP1诱导的NF-κB成分磷酸化以及NF-κB p65亚基的核转位，表明JNK和p38作为NF-κB的上游调节因子参与AIMP1诱导的小胶质细胞激活。NF-κB抑制剂抑制AIMP1诱导的小胶质细胞M1极化。综上所述，AIMP1通过JNK和p38/NF-κB依赖性途径有效诱导M1小胶质细胞激活。这些结果表明，在应激条件下释放的AIMP1可能是诱导神经炎症的病理因素。
