Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption

Uchida, Toshihiro; Mori, Masahiro; Uzawa, Akiyuki; Masuda, Hiroki; Muto, Mayumi; Ohtani, Ryohei; Kuwabara, Satoshi

doi:10.1177/1352458516672015

Cited by 48 publications

(32 citation statements)

References 35 publications

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“…In this context, T. gondii infection may indirectly deregulate signaling pathways critical in controlling vessel stability by (i) affecting RG potential concerning mediation of BBB formation or (ii) disrupting tight junction proteins expression and organization directly in endothelial cells. Increased BBB disruption and permeability have been recently correlated t elevated levels of the pro-inflammatory cytokine IL-6 in the cerebrospinal fluid of human adult individuals affected by neuromyelitis optica and neuropsychiatric systemic lupus erythematosus, and in a rat model of psychosocial stress induction (Uchida et al, 2017; Asano et al, 2017; Schiavone et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Adesse

Marcos

Siqueira

et al. 2018

Preprint

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Congenital toxoplasmosis is a parasitic disease that occurs due vertical transmission of the protozoan Toxoplasma gondii (T. gondii) during pregnancy. The parasite crosses the placental barrier and reaches the developing brain, infecting progenitor, glial, neuronal and vascular cell types. Although the role of Radial glia (RG) neural stem cells in the development of the brain vasculature has been recently investigated, the impact of T. gondii infection in these events is not yet understood. Herein, we studied the role of T. gondii infection on RG cell function and its interaction with endothelial cells. By infecting isolated RG cells with T. gondii tachyzoites, we observed reduced cell proliferation and neurogenesis without affecting gliogenesis levels. Conditioned medium (CM) from RG control cultures increased ZO-1 and β-catenin protein levels and organization on endothelial bEnd.3 cells membranes, which was completely impaired by CM from infected RG, resulting in decreased transendothelial electrical resistance (TEER). Cytokine Bead Array and ELISA assays revealed the presence of increased levels of the pro-inflammatory cytokine IL-6 and reduced levels of anti-inflammatory cytokine TGF-β1 in CM from T.gondii-infected RG cells. Treatment with recombinant TGF-β1 concomitantly with CM from infected RG cultures led to restoration of ZO-1 staining in bEnd.3 cells. Our results suggest that infection of RG cells by T. gondii modulate cytokine secretion, which might contribute to endothelial loss of barrier properties, thus leading to impairment of neurovascular interaction establishment.

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Section: Discussionmentioning

confidence: 99%

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Adesse

Marcos

Siqueira

et al. 2018

Preprint

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“…A minimum of36 independent studies have quantified the concentrations of 86 unique CSF analytes from NMOSD patients [ 134 , 137 , 142 , 164 , 170 , 172 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 ]. Several of these studies corroborate the metabolomic and proteomic observations discussed above.…”

Section: Proteomics In Nmosdmentioning

confidence: 99%

Metabolomic Profiling in Neuromyelitis Optica Spectrum Disorder Biomarker Discovery

Thoman

McKarns

2020

Metabolites

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There is no specific test for diagnosing neuromyelitis optica spectrum disorder (NMOSD), a disabling autoimmune disease of the central nervous system. Instead, diagnosis relies on ruling out other related disorders with overlapping clinical symptoms. An urgency for NMOSD biomarker discovery is underscored by adverse responses to treatment following misdiagnosis and poor prognosis following the delayed onset of treatment. Pathogenic autoantibiotics that target the water channel aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) contribute to NMOSD pathology. The importance of early diagnosis between AQP4-Ab+ NMOSD, MOG-Ab+ NMOSD, AQP4-Ab− MOG-Ab− NMOSD, and related disorders cannot be overemphasized. Here, we provide a comprehensive data collection and analysis of the currently known metabolomic perturbations and related proteomic outcomes of NMOSD. We highlight short chain fatty acids, lipoproteins, amino acids, and lactate as candidate diagnostic biomarkers. Although the application of metabolomic profiling to individual NMOSD patient care shows promise, more research is needed.

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“…Intrathecal levels of IL‐6 correlate with biomarkers for astrocyte loss and anti‐AQP4 antibody titers (Uzawa et al, ) are significantly higher in NMO compared with any other neurological disease (Uzawa et al, ), and are associated with the severity of disease in NMO (Matsushita et al, ) and TM (Dixit et al, ), highlighting the particular importance of this cytokine in NMOSD. IL‐6 mediates BBB breakdown (Uchida et al, ) and promotes the survival of anti‐AQP4 autoantibody‐producing plasmablasts in NMO (Chihara et al, ). In TM, high levels of IL‐6 are produced by astrocytes in the CNS and are accompanied by enhanced levels of nitric oxide (NO) and severe tissue injury (Dixit et al, ; Kaplin et al, ; Wullschleger et al, ).…”

Section: The Response Of Microglia In Il‐6‐ and Ifn‐i‐mediated Neuroimentioning

confidence: 99%

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

West

Viengkhou

Campbell

et al. 2019

Glia

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Microglia are the resident macrophages of the central nervous system (CNS). They are a heterogenous, exquisitely responsive, and highly plastic cell population, which enables them to perform diverse roles. They sense and respond to the local production of many different signals, including an assorted range of cytokines. Microglia respond strongly to interleukin‐6 (IL‐6) and members of the type I interferon (IFN‐I) family, IFN‐alpha (IFN‐α), and IFN‐beta (IFN‐β). Although these cytokines are essential in maintaining homeostasis and for activating and regulating immune responses, their chronic production has been linked to the development of distinct human neurological diseases, termed “cerebral cytokinopathies.” IL‐6 and IFN‐α have been identified as key mediators in the pathogenesis of neuroinflammatory disorders including neuromyelitis optica and Aicardi‐Goutières syndrome, respectively, whereas IFN‐β has an emerging role as a causal factor in age‐associated cognitive decline. One of the key features that unites these diseases is the presence of highly reactive microglia. The current understanding is that microglia contribute to the development of cerebral cytokinopathies and represent an important therapeutic target. However, it remains to be resolved whether microglia have beneficial or detrimental effects. Here we review and discuss what is currently known about the microglial response to IL‐6 and IFN‐I, based on both animal models and clinical studies. Foundational knowledge regarding the microglial response to IL‐6 and IFN‐I is now being used to devise therapeutic strategies to ameliorate neuroinflammation and promote repair: either through targeting microglia, or by targeting the reduction of CNS levels or downstream biological pathways of IL‐6 or IFN‐I.

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Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption

Abstract: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).

Cited by 48 publications

References 35 publications

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Radial Glia cell infection byToxoplasma gondiidisrupts brain microvascular endothelial cell integrity

Metabolomic Profiling in Neuromyelitis Optica Spectrum Disorder Biomarker Discovery

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

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