Institute of Military Cognitive and Brain Sciences, Beijing, 100850, China.
Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Int J Biol Sci. 2018 Nov 2;14(14):1993-2002. doi: 10.7150/ijbs.27459. eCollection 2018.
Macrophage migration plays an essential role in immune system and is also involved in many pathological situations. However, the regulatory mechanism of macrophage migration remains to be elucidated due to its diverse responses to various stimuli. SAK-HV, a multifunctional protein possessing thrombolytic and lipid-lowering activity, can selectively induce the macrophage proliferation. Here, we reported SAK-HV significantly triggered RAW264.7 cells migration through its functional domain of SAK-mutant by activating both c-jun N-terminal kinases (JNK) and nuclear factor-κB (NF-κB) pathways. Meanwhile, SAK-HV upregulated the expression of some effector proteins, among which only the expression of Monocyte chemoattractant protein-1 (MCP-1) was inhibited by the blockade of JNK and NF-κB pathways. Further research showed that MCP-1 promoted migration ultimately by interacting with Chemokine (C-C motif) Receptor 2 (CCR2) in an autocrine manner. In summary, SAK-HV induced RAW264.7 cells migration through its SAK-mutant domain, during which MCP-1 chemokine mediated by JNK and NF-κB pathways played a key role. These results revealed a novel effect of SAK-HV on modulating macrophage migration and also deepened the understanding of its pharmacodynamics.
巨噬细胞迁移在免疫系统中起着至关重要的作用，也涉及许多病理情况。然而，由于其对各种刺激的多样化反应，巨噬细胞迁移的调节机制仍有待阐明。SAK-HV 是一种具有溶栓和降血脂活性的多功能蛋白，可选择性地诱导巨噬细胞增殖。在这里，我们通过 SAK 突变体的功能域发现 SAK-HV 可以显著触发 RAW264.7 细胞的迁移，通过激活 c-jun N 端激酶（JNK）和核因子-κB（NF-κB）通路。同时，SAK-HV 上调了一些效应蛋白的表达，其中只有 JNK 和 NF-κB 通路被阻断时，单核细胞趋化蛋白-1（MCP-1）的表达才被抑制。进一步的研究表明，MCP-1 通过自分泌与趋化因子（C-C 基序）受体 2（CCR2）相互作用最终促进迁移。总之，SAK-HV 通过其 SAK 突变域诱导 RAW264.7 细胞迁移，在此过程中，MCP-1 趋化因子通过 JNK 和 NF-κB 通路发挥关键作用。这些结果揭示了 SAK-HV 对调节巨噬细胞迁移的新作用，并加深了对其药效学的理解。
