Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6

Uzawa, Akiyuki; Mori, Masahiro; Arai, Kimihito; Sato, Yasunori; Hayakawa, Sohachiro; Masuda, Saeko; Taniguchi, Junko; Kuwabara, Satoshi

doi:10.1177/1352458510379247

Cited by 290 publications

(267 citation statements)

References 42 publications

(51 reference statements)

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“…Our further demonstration that astrocytes exposed to NMO-F(ab′) 2 release IL-6, without internalizing AQP4, is consistent with the documented proinflammatory response stimulated in astrocytes as an outcome of AQP4 clustering: secretion of complement components, chemokines, and cytokines (13,14). IL-6 is a critical mediator of CNS inflammation in NMO (23,24), as evidenced by the therapeutic benefit of monoclonal IgG blockade of IL-6 (25). Ex vivo, IL-6 released by astrocytes exposed to NMO-IgG reduced CNS capillary endothelial barrier function, increased CCL2 and CXCL8 production, and promoted leukocyte transmigration under flow conditions; these effects were neutralized by IL-6-specific IgG (12).…”

Section: Discussionsupporting

confidence: 59%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.N euromyelitis optica (NMO) is a relapsing inflammatory autoimmune demyelinating disease of the central nervous system (CNS), long considered a severe form of multiple sclerosis (MS). Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2, 3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4, 5).The aquaporin-4 (AQP4) water channel is the CNS target (4). Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1, 6-11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6-12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1). The blood-brain barrier (BBB) does not absolutely restrict IgG entry into the CNS, but it does exclude macromolecular C1q, essential for activating the classical complement cascade.Experimental studies of lesional events in vitro and in animal models of NMO have emphasized complement-mediated inflammation and astrocyte cytolysis, late events associated with extensive BBB disruption. A neglected potential initiator of NMO pathophysiology is the AQP4-IgG-activated astrocyte's response: synthesis and secretion of complement, cytokines, chemokines (12-14), and inflammatory mediators attracting NMO-characteristic gra...

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Section: Discussionsupporting

confidence: 59%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies have revealed that the CSF levels of IL-6 and IL-8 are significantly elevated in patients with neuromyelitis optica (NMO) compared with that observed in patients with multiple sclerosis or non-inflammatory neurological diseases (23). None of our patients with NB exhibited optic neuritis or spinal cord lesions.…”

Section: Discussionmentioning

confidence: 58%

Changes in Biomarkers Focused on Differences in Disease Course or Treatment in Patients with Neuro-Behçet's Disease

Hirohata

Kikuchi

2012

Intern. Med.

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Objective Neurological manifestations of Behçet's disease (NB) are serious complications. However, their pathogenesis remains unclear. The current study examined the levels of proinflammatory cytokines, including IL-1β, IL-6, IL-8 and TNF-α, in cerebrospinal fluid (CSF). Methods CSF cytokines were measured using an enzyme-linked immunosorbent assay. CSF was obtained from 17 patients with acute NB, 19 patients with chronic progressive NB and 20 patients with noninflammatory neurological diseases, including cerebrovascular disease, cervical spondylosis and degenerative diseases. Results CSF total cell counts and polymorph nuclear leukocyte counts were significantly lower in the patients with chronic progressive NB than in those with acute NB. The CSF levels of IL-6 and IL-8 were markedly elevated in the NB patients compared with those measured in the control patients. There were no significant differences in the CSF levels of IL-6 and IL-8 between the patients with acute NB and those with chronic progressive NB. In contrast, there were no significant differences in the CSF levels of IL-1β and TNF-α among the control, acute NB and chronic progressive NB patients. Consistently, the CSF levels of IL-6 and IL-8 were significantly decreased following successful treatment in both acute NB and chronic progressive NB patients, whereas the CSF levels of IL-1β and TNF-α were not changed significantly. Of note, the CSF levels of IL-6 were significantly correlated with the CSF levels of IL-8 in the patients with acute NB (r =0.7647, p =0.0003) but not in the patients with chronic progressive NB (r =0.1343, p =0.5835). Conclusion These results indicate that CSF IL-6 and IL-8 play important roles in the pathogenesis of NB. However, the data also suggest that the mechanisms underlying the elevation of CSF IL-6 and IL-8 might be different in patients with acute NB and those with chronic progressive NB.

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“…Consistent with this report, in our study, AxD astrocytes from patient iPSCs exhibited increased amounts of secreted GM-CSF, IL5, IL6, and TNFα. GM-CSF, IL6, and TNFα are well known as proinflammatory cytokines and are upregulated in various kinds of white matter diseases, including multiple sclerosis (MS) and neuromyelitis optica (NMO) [25][26][27][28]. IL-5 is a Th2 cell-type cytokine that is secreted by astrocytes and microglia [29], turning on the switch of inflammatory response by activating microglia to upregulate inflammatory response in the brain, cooperating with GM-CSF [30,31].…”

Section: Discussionmentioning

confidence: 99%

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Kondo

Funayama

Miyake

et al. 2017

Journal of the Neurological Sciences

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Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.

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Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6

Abstract: Different immunological status and pathophysiologies exist between NMO and MS, and IL-6 may play important roles in the pathogenesis of NMO.

Cited by 290 publications

References 42 publications

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Changes in Biomarkers Focused on Differences in Disease Course or Treatment in Patients with Neuro-Behçet's Disease

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

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