CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy

Furukawa, Takahiro; Matsui, Naoko; Fujita, Koji; Nodera, Hiroyuki; Shimizu, Fumitaka; Miyamoto, Katsuichi; Takahashi, Yukitoshi; Kanda, Takashi; Kusunoki, Susumu; Izumi, Yuishin; Kaji, Ryuji

doi:10.1212/nxi.0000000000000138

Cited by 39 publications

(27 citation statements)

References 40 publications

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“…We did observe increased pro-inflammatory TNF-α and IL-17 and immune-regulatory IL-10 in ALS CSF, which is in agreement with earlier reported findings for TNF-α [ 61 , 62 ], IL-10 [ 63 ], and IL-17 [ 46 , 63 – 65 ]. We also found a negative correlation between CSF TNF-α and disease duration not previously reported, suggesting that higher levels of TNF-α were predictive of shorter disease duration and faster progression.…”

Section: Discussionsupporting

confidence: 93%

Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function

Drannik

Martin

Peterson³

et al. 2017

PLoS ONE

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Sonic hedgehog (Shh) is a morphogen essential to the developing nervous system that continues to play an important role in adult life by contributing to cell proliferation and differentiation, maintaining blood-brain barrier integrity, and being cytoprotective against oxidative and excitotoxic stress, all features of importance in amyotrophic lateral sclerosis (ALS). ALS is a fatal disease characterized by selective loss of motor neurons due to poorly understood mechanisms. Evidence indicates that Shh might play an important role in ALS, and that Shh signaling might be also adversely affected in ALS. Since little is known about the functional status of Shh pathway in patients with ALS, we therefore sought to determine whether Shh protein levels or biological activity in cerebrospinal fluid (CSF) was less in ALS patients than controls, and whether these measures could be correlated with ALS disease severity and disease progression, and with other CSF analytes of biological interest in ALS. Comparing Shh levels in the CSF of normal controls (n = 13), neurological controls (n = 12), and ALS patients (n = 9) measured by ELISA, we found that CSF Shh levels were not different between controls and ALS patients. However, when assessing Shh biological activity in CSF using in vitro cell-based assays, which measure Shh activity as inducible Gli-driven luminescence, we found that in the presence of exogenous recombinant Shh or the Shh agonist, purmorphamine, the inducible activity of CSF was significantly augmented in the control groups as expected, but not in the ALS group, suggesting the presence of an inhibitor of Shh signaling in ALS CSF samples. Since purmorphamine acts on Smoothened, downstream of Shh and its receptor Patched, the inhibitory action is downstream of Smoothened. Our results also demonstrated that while the inhibitory effect of ALS CSF on Shh signaling did not correlate significantly with ALS disease characteristics, the levels of IL-1β and TNF-α did. In addition to being significantly elevated in ALS CSF, these cytokines negatively correlated with the disease duration, whereas GDF11 was a favorable predictor of ALS clinical score. We also found that TNF-α significantly inhibited Shh biological activity in vitro, potentially suggesting a novel role of TNF-α in ALS pathogenesis. Collectively, this is the first report demonstrating that Shh signaling in CSF of ALS patients is compromised.

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Section: Discussionsupporting

confidence: 93%

Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function

Drannik

Martin

Peterson³

et al. 2017

PLoS ONE

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“…While the precise cell type to release each inflammatory mediator that is increasd in the setting of ALS pathology is not known, the detection of these markers in CSF and serum is likely to be a surrogate marker of glial pathology and disease activity. In ALS patients, CSF IL‐4, IL‐7, IL‐10, IL‐17, and G‐CSF were significantly elevated (Furukawa et al, ). It was noted that titers of IL‐4 and IL‐10 were particularly higher in patients with mild symptoms suggesting a potential unique cytokine signature in patients with a slower progressing disease.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Glial biomarkers in human central nervous system disease

Garden

Campbell

2016

Glia

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There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments.

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“…Likewise, increased levels of CCL11 are found in neurodegenerative diseases, where CSF concentrations of CCL11 correlate with the disease progress [5,14,15]. On the contrary, increased levels of CCL11 in amyotrophic lateral sclerosis (ALS) negatively correlate with disease progression [16]. Under conditions of experimental autoimmune encephalitis in rats, CCL11 modulates the immune response by reducing both demyelination and cumulative microglial activation [17].…”

Section: Introductionmentioning

confidence: 99%

CCL11 Differentially Affects Post-Stroke Brain Injury and Neuroregeneration in Mice Depending on Age

Lieschke

Zechmeister

Haupt

et al. 2019

Cells

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CCL11 has recently been shown to differentially affect cell survival under various pathological conditions including stroke. Indeed, CCL11 promotes neuroregeneration in neonatal stroke mice. The impact of CCL11 on the adult ischemic brain, however, remains elusive. We therefore studied the effect of ectopic CCL11 on both adolescent (six-week) and adult (six-month) C57BL6 mice exposed to stroke. Intraperitoneal application of CCL11 significantly aggravated acute brain injury in adult mice but not in adolescent mice. Likewise, post-stroke neurological recovery after four weeks was significantly impaired in adult mice whilst CCL11 was present. On the contrary, CCL11 stimulated gliogenesis and neurogenesis in adolescent mice. Flow cytometry analysis of blood and brain samples revealed a modification of inflammation by CCL11 at subacute stages of the disease. In adolescent mice, CCL11 enhances microglial cell, B and T lymphocyte migration towards the brain, whereas only the number of B lymphocytes is increased in the adult brain. Finally, the CCL11 inhibitor SB297006 significantly reversed the aforementioned effects. Our study, for the first time, demonstrates CCL11 to be a key player in mediating secondary cell injury under stroke conditions. Interfering with this pathway, as shown for SB297006, might thus be an interesting approach for future stroke treatment paradigms.

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CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy

Cited by 39 publications

References 40 publications

Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function

Cerebrospinal fluid from patients with amyotrophic lateral sclerosis inhibits sonic hedgehog function

Glial biomarkers in human central nervous system disease

CCL11 Differentially Affects Post-Stroke Brain Injury and Neuroregeneration in Mice Depending on Age

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