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

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. © 2017 the author(s).