Upregulation of cathepsin S in psoriatic keratinocytes.

Cathepsin S (CATS) is a cysteine protease, well known for its role in MHC class II-mediated antigen presentation and extracellular matrix degradation. Disturbance of the expression or metabolism of this protease is a concomitant feature of several diseases. Given this importance we studied the localization and regulation of CATS expression in normal and pathological human/mouse skin. In normal human skin CATS-immunostaining is mainly present in the dermis and is localized in macrophages, Langerhans, T- and endothelial cells, but absent in keratinocytes. In all analyzed pathological skin biopsies, i.e. atopic dermatitis, actinic keratosis and psoriasis, CATS staining is strongly increased in the dermis. But only in psoriasis, CATS-immunostaining is also detectable in keratinocytes. We show that cocultivation with T-cells as well as treatment with cytokines can trigger expression and secretion of CATS, which is involved in MHC II processing in keratinocytes. Our data provide first evidence that CATS expression (i) is selectively induced in psoriatic keratinocytes, (ii) is triggered by T-cells and (iii) might be involved in keratinocytic MHC class II expression, the processing of the MHC class II-associated invariant chain and remodeling of the extracellular matrix. This paper expands our knowledge on the important role of keratinocytes in dermatological disease.

Intra- versus extracellular effects of microglia-derived cysteine proteases in a conditioned medium transfer model.

Activated microglia release inflammatory mediators that display either beneficial or harmful effects on neuronal survival and signaling. In the present study we demonstrate that exposure to lipopolysaccharide leads to an increase in the lysosomal cysteine proteases, cathepsin B, K, S, and X, in culture supernatants of the microglia cell line BV-2. In addition, we observed an up-regulation of cathepsins in the cytoplasmic fraction in response to stimulation with lipopolysaccharide. Conditioned medium from these cells was toxic to the neuroblastoma cell line Neuro2a. Experiments with membrane-permeable and membrane-impermeable cysteine protease inhibitors suggested that blocking extracellular cathepsins had no effect on microglia-mediated neuron death in this medium transfer model. However, intracellular cathepsins seem to trigger the release of neurotoxic factors. In lipopolysaccharide-stimulated BV-2 cells, inhibition of intracellular cathepsins significantly diminished microglial activation characterized by reduced expression of different proinflammatory cytokines, thereby reducing the neurotoxic effects of the medium. This hitherto unknown intracellular effect of cysteine proteases in activated microglia might connect chronic neuroinflammation with neurodegeneration.

Upregulation of cathepsin S in the aging and pathological nervous system of mice.

Cathepsins have long been regarded enzymes that are primarily involved in general protein turnover within lysosomes. However, more recently, their differential cell and tissue distributions suggest that at least some of them participate in specific cellular processes. Cathepsin S (CATS) is mainly expressed in cells of mononuclear phagocytotic origin and plays a major role in the MHC-II-mediated antigen presentation. Although a central role for CATS in brain function has also been suggested, its localization and regulation in the central nervous system are still poorly understood. In the present study we investigated the regional and cellular expression of CATS in normal, aging and pathological mouse brain. Our studies show that CATS is expressed throughout the adult mouse brain, in particular in microglial cells. In aged mice, CATS protein expression increases in these cells. In addition, it became apparent that in old mice a larger number of neuronal cells stained positive for this protease. At the subcellular level, CATS immunostaining accumulated in granules, indicating a lysosomal localization. In a transgenic mouse model of amyotrophic lateral sclerosis expressing mutant superoxide dismutase 1 (SOD1), CATS transcript and protein levels were significantly upregulated in spinal cord and lower brain regions displaying neuronal degeneration. The majority of strongly immunopositive cells in these regions exhibited microglial morphology. These results suggest that CATS participates in inflammatory processes accompanying aging and pathologies of the CNS.

Differential expression of Cathepsin S and X in the spinal cord of a rat neuropathic pain model.

BACKGROUND: Ample evidence suggests a substantial contribution of cellular and molecular changes in the spinal cord to the induction and persistence of chronic neuropathic pain conditions. While for a long time, proteases were mainly considered as protein degrading enzymes, they are now receiving growing interest as signalling molecules in the pain pathology. In the present study we focused on two cathepsins, CATS and CATX, and studied their spatiotemporal expression and activity during the development and progression of neuropathic pain in the CNS of the rat 5th lumbar spinal nerve transection model (L5T). RESULTS: Immediately after the lesion, both cathepsins, CATS and CATX, were upregulated in the spinal cord. Moreover, we succeeded in measuring the activity of CATX, which was substantially increased after L5T. The differential expression of these proteins exhibited the same spatial distribution and temporal progression in the spinal cord, progressing up to the medulla oblongata in the late phase of chronic pain. The cellular distribution of CATS and CATX was, however, considerably different. CONCLUSION: The cellular distribution and the spatio-temporal development of the altered expression of CATS and CATX suggest that these proteins are important players in the spinal mechanisms involved in chronic pain induction and maintenance.

Differential expression of cathepsin X in aging and pathological central nervous system of mice.

Increasing evidence of a fundamental influence of cathepsins on inflammation has drawn interest in a thorough understanding of their role in physiological and pathological processes. Even though the number of identified cathepsins has more than doubled in the last years, information about their expression, regulation and function in the brain is still incomplete. In the present study we analyzed the regional, cellular and subcellular localization and the activity of the recently discovered cathepsin X in the normal, developing and pathological mouse brain. Our results show that CATX is: (i) is expressed in almost all cells in the mouse brain with a preference for glial cells; (ii) already widely expressed early in development and age-dependently upregulated in amount and activity; (iii) prominently localized in the lysosomal system but also scattered in the somal cytoplasm in the aged brain; (iv) upregulated in numerous glial cells of degenerating brain regions in a transgenic mouse model of amyotrophic lateral sclerosis; and (v) associated with plaques in a transgenic mouse model and in Alzheimer patients. These results strongly suggest that cathepsin X is an important player in degenerative processes during normal aging and in pathological conditions.