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J Neuroinflammation. 2018 Apr 27;15(1):125. doi: 10.1186/s12974-018-1162-0.

Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder.

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Department of Neurology, Osaka University Graduate School of Medicine, D4, 2-2 Yamadaoka, Osaka, 565-0871, Japan.
Department of Neurology, Osaka General Medical Center, Osaka, Japan.
Department of Neurology, Kinki University Graduate School of Medicine, Osaka, Japan.
National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Mathematics and Computer Science, Kagoshima University Graduate School of Science and Technology, Kagoshima, Japan.
Center for Information and Neural Networks (CiNet), National Institute of Information and Communications Technology (NICT), Osaka University, Osaka, Japan.
Department of Neurology, Toyama University, Toyama, Japan.
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Neurology, Osaka University Graduate School of Medicine, D4, 2-2 Yamadaoka, Osaka, 565-0871, Japan.
Department of Neurology, Osaka University Graduate School of Medicine, D4, 2-2 Yamadaoka, Osaka, 565-0871, Japan.



Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients.


Using quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre- and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1β production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1β production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes.


Extracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1β from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1β production depends on specific innate immune pathways.


Extracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.


Innate immunity; Mitochondrial DNA; NMOSD

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