Mitochondrial DNA enhance innate immune responses in neuromyelitis optica by monocyte recruitment and activation
Mitochondrial DNA enhance innate immune responses in neuromyelitis optica by monocyte recruitment and activation
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DOI：
10.1038/s41598-020-70203-x
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发表时间：
2020-08-06
影响因子：
4.6
通讯作者：
Mochizuki, Hideki
中科院分区：
文献类型：
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作者：
Shimizu, Mikito;Okuno, Tatsusada;Mochizuki, Hideki
虽然最近的研究表明单核细胞参与加速视神经肌萎缩症谱系障碍（NMOSD）的病变形成，但先天免疫系统激活的确切机制仍然难以捉摸。因此，在本研究中，我们的目的是从先天免疫激活的角度阐明NMOSD发病机制。我们从NMOSD患者CSF中的浆母细胞中建立了抗AQP4重组自身抗体（Ab）。用抗AQP4抗体处理的人星形胶质细胞产生显著量的CCL 2，并有助于单核细胞的有效募集。此外，线粒体DNA（mtDNA），激活单核细胞通过Toll样受体9（TLR9），从星形胶质细胞与抗AQP4抗体处理释放。mtDNA进一步增强单核细胞的CCL2产生，并且证明mtDNA浓度与NMOSD患者CSF中单核细胞募集的效率相关。总之，这些观察结果强调了从抗AQP4 Ab损伤的星形胶质细胞释放的mtDNA在通过先天免疫途径建立单核细胞募集和激活的炎症循环中具有核心作用。
Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient's CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.