Stefin B (cystatin B) is an endogenous cysteine cathepsin inhibitor localized in the cytosol, mitochondria and nucleus. Its expression is upregulated upon macrophage activation and cellular stress. Mutations in the gene of stefin B are associated with the neurodegenerative disease known as Unverricht-Lundborg disease (EPM1). It was reported that early microglial activation precedes neuronal loss in the brain of the stefin B-deficient mice, implying a role of the inhibitor at the cross-talk between microglia and cerebellar cells. Detailed analysis of microglial activation in stefin B-deficient microglia showed a significantly higher proportion of both pro-inflammatory M1 and anti-inflammatory M2 microglia in stefin B-deficient mouse brain compared with control mice. In our recent work, we demonstrated that stefin B-deficient mice were significantly more sensitive to the lethal lipopolysaccharide (LPS)-induced sepsis, due to increased caspase-11 expression and secreted higher amounts of pro-inflammatory cytokines IL-1β and IL-18. Upon LPS stimulation, stefin B was targeted into the mitochondria, and the lack of stefin B resulted in the increased destabilization of the mitochondrial membrane potential and mitochondrial superoxide generation. The increased caspase-11 gene expression and better pro- inflammatory caspase-1 and -11 activation determined in stefin B deficient bone marrow-derived macrophages resulted in enhanced non-canonical inflammasome activation. Since signaling pathways in macrophages could be compared to the ones in microglia we propose that inflammasome activation could play an important role in the pathogenesis of EPM1.