Cystatin C and cathepsin B in CSF from patients with inflammatory  neurologic diseases

Nagai, Atsushi; Murakawa, Yohko; Terashima, Masaharu; Shimode, Koichi; Umegae, Nobuyuki; Takeuchi, Hiromi; Kobayashi, Shotai

doi:10.1212/wnl.55.12.1828

Cited by 83 publications

(65 citation statements)

References 29 publications

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“…In line with our results are reports on the protective effects of cathepsin B inhibition in animal models of acute and chronic neurodegenerative disorders, including cerebral ischemia and Alzheimer's disease (60,61). Moreover, high cathepsin B activity was detected in CSF samples from patients with neuroinflammatory diseases such as multiple sclerosis (62). Inflammasome activation plays an important role in the three diseases listed above by exacerbating brain inflammation (54,63,64).…”

Section: Discussionsupporting

confidence: 89%

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

Hoegen

Tremel

Klein

et al. 2011

The Journal of Immunology

193

166

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Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18–binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1β and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1β expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease.

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Section: Discussionsupporting

confidence: 89%

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

Hoegen

Tremel

Klein

et al. 2011

The Journal of Immunology

193

166

View full text Add to dashboard Cite

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“…Accordingly, alterations in protein expression, post-translational modification or turn-over within the tissue of the nervous system may be mirrored in corresponding changes in CSF protein content. So far, several candidate markers associated with different aspects of the complex disease pathology like inflammation including chemokine reactions and complement activation, but also blood-CSF barrier dysfunction, demyelination or neuro-axonal damage have been investigated [2,23,28,30,31,45,46,51,54,65,75]. Apart from elucidating aspects of disease pathology, some of these markers were suggested to have clinical relevance with regard to prognosis of disease [28,44,47,51].…”

Section: ■ Guillain-barré Syndromementioning

confidence: 99%

Cerebrospinal fluid biomarkers in Guillain-Barré syndrome – Where do we stand?

Brettschneider

Petzold²,

Süßmuth

et al. 2009

J Neurol

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Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy affecting the myelin-protein sheathing and the axons themselves to various degrees. Damage to these structures causes biomarkers to be released into the adjacent body fluid compartment. In case of the proximal nerve roots these biomarkers diffuse into the cerebrospinal fluid (CSF). Here we review the literature on CSF biomarkers in GBS, including a discussion of CSF basic findings, myelin sheath-associated markers (myelin basic protein), axonal damage markers (neurofilaments, tau, anti-ganglioside antibodies), glial and neuronal markers (neuron specific enolase, 14-3-3 proteins, S100B, hypocretin-1), immunological markers (different chemokines and complement factors, cystatin C, tumor necrosis factor-alpha) as well as recent advances in the field of CSF proteome analysis in GBS. Second, the different pathophysiological mechanisms reflected by these biomarkers are discussed. Finally, candidate biomarkers are reviewed with regard to their clinical relevance to act as a surrogate for the disease process, their value for improving prognostic accuracy and their potential to be used as predictors of treatment response.

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“…Prior proteomic investigations utilizing 2-DE and MALDI-TOF-MS have identified individual proteins present in the CSF of specific diseases, such as Alzheimer's disease, Parkinson's disease, CJD, chronic pain, and primary CNS neoplasms [15,26,[27][28][29]. However, direct comparisons of CSF protein alterations across CNS disease states have not been adequately undertaken, raising legitimate questions regarding the specificity of these CSF markers [30].…”

Section: Discussionmentioning

confidence: 99%

“…One possibility is that the neoplastic tissue and surrounding CNS structures do not produce these proteins. Alternatively, accelerated degradation or clearance of these proteins may occur following the increased expression and activation of CSF proteases in neoplastic diseases, including the cathepsins, matrix metalloproteinases (MMPs), and plasminogen activators [27,31].…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, we found that cystatin C was present in the large majority of nondiagnostic and reactive/inflammatory samples, with the highest-intensity bands noted in inflammatory disease. Others have demonstrated increased expression of cystatin C in inflammatory, infectious, and degenerative CNS diseases, raising the possibility of it use as a marker of non-neoplastic CSF [18,27,28], while two independent studies have yielded conflicting results regarding cystatin C as a diagnostic marker in pain syndromes [31].…”

Section: Discussionmentioning

confidence: 99%

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Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers

et al. 2006

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CNS diseases are often accompanied by changes in the protein composition of cerebrospinal fluid (CSF). SELDI-TOF-MS provides an approach for identifying specific protein markers of disease in biological fluids. We compared the CSF proteomes from patients with neoplastic and reactive/inflammatory CNS diseases to identify potential biomarkers. SELDI-TOF-MS was performed on CSF derived from lumbar puncture of 32 patients, including 10 with CNS malignancies, 12 with inflammatory or reactive conditions, and 10 with unknown CNS disease. Using the SAX-2 (strong anionic exchange) chip, we uncovered three conserved protein peak ranges within each disease category. For neoplastic diseases, we identified conserved peaks at 7.5-8.0 kDa (9/10 samples), 15.1-15.9 kDa (8/10 samples), and 30.0-32.0 kDa (5/10 samples). In reactive/inflammatory diseases, conserved peaks were found at 6.7-7.1 kDa (10/12 samples), 11.5-11.9 kDa (12/12 samples), and 13.3-13.7 kDa (9/12 samples). A protein from the 30.0 to 32.0 kDa peak range found in neoplastic CSF was identified by MALDI analysis as carbonic anhydrase, a protein overexpressed in many malignancies including high-grade gliomas. Similarly, cystatin C was identified in the 13.3-13.7 kDa peak range in non-neoplastic CSF and was most prominent in inflammatory conditions. Our approach provides a rational basis for identifying biomarkers that could be used for detection, diagnosis, and monitoring of CNS diseases.

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Cystatin C and cathepsin B in CSF from patients with inflammatory neurologic diseases

Abstract: Cystatin C levels in CSF measured by ELISA may help the physician recognize GBS, CIDP, and MS. Decreased levels of cystatin C may be related to the high levels of cathepsin B activity seen in the CSF of patients with GBS, CIDP, and MS.

Cited by 83 publications

References 29 publications

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

Cerebrospinal fluid biomarkers in Guillain-Barré syndrome – Where do we stand?

Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markers

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