Related Experiment Video
Updated: Mar 2, 2026
Author Spotlight: Novel Assay for Studying B-Cell Responses in Multiple Sclerosis Research
Published on: December 1, 2023
A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple
Euan R O Allan1, Rhiannon I Campden1,2, Benjamin W Ewanchuk1,2
1Snyder Institute for Chronic Disease, University of Calgary, Calgary, AB, T2N 4 N1, Canada.
Background:
Hypomethylation of the cathepsin Z locus has been proposed as an epigenetic risk factor for multiple sclerosis (MS). Cathepsin Z is a unique lysosomal cysteine cathepsin expressed primarily by antigen presenting cells. While cathepsin Z expression has been associated with neuroinflammatory disorders, a role for cathepsin Z in mediating neuroinflammation has not been previously established.
Methods:
Experimental autoimmune encephalomyelitis (EAE) was induced in both wildtype mice and mice deficient in cathepsin Z. The effects of cathepsin Z-deficiency on the processing and presentation of the autoantigen myelin oligodendrocyte glycoprotein, and on the production of IL-1β and IL-18 were determined in vitro from cells derived from wildtype and cathepsin Z-deficient mice. The effects of cathepsin Z-deficiency on CD4+ T cell activation, migration, and infiltration to the CNS were determined in vivo. Statistical analyses of parametric data were performed by one-way ANOVA followed by Tukey post-hoc tests, or by an unpaired Student's t test. EAE clinical scoring was analyzed using the Mann-Whitney U test.
Results:
We showed that mice deficient in cathepsin Z have reduced neuroinflammation and dramatically lowered circulating levels of IL-1β during EAE. Deficiency in cathepsin Z did not impact either the processing or the presentation of MOG, or MOG- specific CD4+ T cell activation and trafficking. Consistently, we found that cathepsin Z-deficiency reduced the efficiency of antigen presenting cells to secrete IL-1β, which in turn reduced the ability of mice to generate Th17 responses-critical steps in the pathogenesis of EAE and MS.
Conclusion:
Together, these data support a novel role for cathepsin Z in the propagation of IL-1β-driven neuroinflammation.
Insights
Cathepsin Z deficiency reduces neuroinflammation in multiple sclerosis models by lowering IL-1β. This highlights cathepsin Z
Area of Science:
- Neuroimmunology
- Epigenetics
- Inflammation
Background:
- Hypomethylation of the cathepsin Z locus is a potential epigenetic risk factor for multiple sclerosis (MS).
- Cathepsin Z, a lysosomal cysteine cathepsin, is primarily expressed by antigen-presenting cells and linked to neuroinflammatory disorders.
- Its specific role in mediating neuroinflammation remained unestablished.
Purpose of the Study:
- To investigate the role of cathepsin Z in neuroinflammation and experimental autoimmune encephalomyelitis (EAE), a model for MS.
- To determine the impact of cathepsin Z deficiency on antigen presentation and cytokine production.
- To elucidate the effect of cathepsin Z deficiency on T cell responses in the context of neuroinflammation.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) was induced in wildtype and cathepsin Z-deficient mice.
- In vitro analysis of autoantigen processing, presentation, and cytokine (IL-1β, IL-18) production by antigen-presenting cells.
- In vivo assessment of CD4+ T cell activation, migration, and central nervous system (CNS) infiltration.
Main Results:
- Mice deficient in cathepsin Z exhibited reduced neuroinflammation and significantly lower circulating IL-1β levels during EAE.
- Cathepsin Z deficiency did not affect myelin oligodendrocyte glycoprotein (MOG) processing, presentation, or MOG-specific CD4+ T cell activation and trafficking.
- Antigen-presenting cells lacking cathepsin Z showed reduced IL-1β secretion, impairing Th17 responses crucial for EAE and MS pathogenesis.
Conclusions:
- Cathepsin Z plays a novel role in promoting IL-1β-driven neuroinflammation.
- Targeting cathepsin Z may offer a therapeutic strategy for MS by modulating IL-1β production and Th17 responses.
More Related Videos
08:17Author Spotlight: Unveiling the Pathway Linking Obesity to Autoimmune Inflammation in Multiple Sclerosis
Published on: February 23, 2024
09:46Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
