Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder

Abstract

BackgroundNeuromyelitis 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.MethodsUsing 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.ResultsExtracellular 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.ConclusionExtracellular 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1162-0) contains supplementary material, which is available to authorized users.

WITHDRAWN: ATP mediates neuropathic pain in neuromyelitis optica via microglial activation

“…CSF levels of HMGB1, a DAMP, are higher in NMOSD patients than in MS and ONDs patients [19]. In addition, the mtDNA level is speci cally elevated in NMOSD CSF [7]. Cellular stress and necrosis are thought to be major contributors to DAMPs release.…”

“…Activated microglia play essential roles in neuropathic pain development and are a major source of IL-1β production [7]. Therefore, we next investigated whether inhibition of microglial activation would alleviate neuropathic pain in NMOSD rat model.…”

“…Anti-aquaporin4 autoantibody (AQP4-Ab) plays a pathogenic role in NMOSD [4][5][6]. We showed previously that mitochondrial DNA (mtDNA), a damage-associated molecular pattern (DAMP), is released by dying astrocytes in an AQP4-Ab-dependent manner and further augments in ammation via innate immune receptors [7]. Several DAMPs, including ATP, are related to neuropathic pain [8], and the pivotal roles of ATP and purinergic receptors have been demonstrated in a peripheral neuropathic pain model [9].…”

Involvement of the Spinal Cord in Primary Mitochondrial Disorders: A Neuroimaging Mimicker of Inflammation and Ischemia in Children

“…Moreover, transfected cells that express AQP4 when incubated with serum from NMOSD AQ4-Ab-positive patients were shown to release mtDNA. 24 NMOSD AQP4-Ab-negative patients may show similar imaging findings, including spinal cord features resembling positive AQP4-Ab. 18 Furthermore, primary mitochondrial dysfunction may induce microglial activation.…”

Mitochondria–A target for attenuation of astrocyte pathology

“…Recently mitochondrial dysfunction has been suggested to play a role in disease progression, disability level and cognitive impairment (Foolad et al, 2020). Mitochondrial DNA in cerebrospinal fluid was elevated in the acute phase of NMOSD (Yamashita et al, 2018) and associated to disease severity (Peng et al, 2020). Additionally, an altered energy metabolism has been associated to disease (Jurynczyk et al, 2017;Kim et al, 2017).…”