A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis

Abstract

BackgroundHypomethylation 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.MethodsExperimental 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.ResultsWe 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.ConclusionTogether, these data support a novel role for cathepsin Z in the propagation of IL-1β-driven neuroinflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0874-x) contains supplementary material, which is available to authorized users.

Upregulation of Cysteine Protease Cathepsin X in the 6-Hydroxydopamine Model of Parkinson’s Disease

“…Furthermore, a comprehensive comparative gene expression analysis of mouse models of multiple sclerosis, AD, and stroke, found that cathepsin X is one of the 18 genes whose expression is increased in all three models of neuroinflammation ( Tseveleki et al, 2010 ). Additionally, Allan et al (2017) showed that mice deficient in cathepsin X have reduced neuroinflammation and dramatically lowered circulating levels of interleukin 1β during experimental autoimmune encephalomyelitis, supporting in vitro studies of novel role of cathepsin X in neuroinflammation ( Pišlar et al, 2017 ). Nevertheless, other experimental models for neurodegenerative diseases, such as for PD, have described the upregulation of the other lysosomal peptidases [reviewed in Pislar and Kos (2014) ].…”

Cathepsin B Is Required for NLRP3 Inflammasome Activation in Macrophages, Through NLRP3 Interaction

“…*p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001, no symbol, not significant. production by macrophages under cholesterol crystals, ATP, MSU, or Alum treatments (Duewell et al, 2010;Oleszycka et al, 2016;Allan et al, 2017). However, these studies didn't explore whether these enzymes are required for NLRP3 inflammasome activation and/or IL-1β secretion.…”

Domestication modulates the expression of genes involved in neurogenesis in high‐quality eggs of Sander lucioperca

“…The qPCR‐validated genes related to the central nervous system that were significantly upregulated in domesticated fish were reported to be responsible for the protection of neurons ( camk2b ; Fang, Feng, Zhao, & Liu, 2014), synaptic plasticity ( ctnna2 ; Terracciano et al, 2011), and were found to be involved in counteracting neuroinflammation ( ctsz ; Allan et al, 2017). The genes that were upregulated in eggs from wild broodstock were reported to regulate thalamocortical axon branching ( ntn4 ; Hayano et al, 2014) and are known to be crucial for normal brain development ( gabrb1 ; Halder et al, 2015).…”