Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury

Abstract

Cathepsin(Cat)-S processing of the invariant chain-MHC-II complex inside antigen presenting cells is a central pathomechanism of autoimmune-diseases. Additionally, Cat-S is released by activated-myeloid cells and was recently described to activate protease-activated-receptor-(PAR)-2 in extracellular compartments. We hypothesized that Cat-S blockade targets both mechanisms and elicits synergistic therapeutic effects on autoimmune tissue injury. MRL-(Fas)lpr mice with spontaneous autoimmune tissue injury were treated with different doses of Cat-S inhibitor RO5459072, mycophenolate mofetil or vehicle. Further, female MRL-(Fas)lpr mice were injected with recombinant Cat-S with/without concomitant Cat-S or PAR-2 blockade. Cat-S blockade dose-dependently reversed aberrant systemic autoimmunity, e.g. plasma cytokines, activation of myeloid cells and hypergammaglobulinemia. Especially IgG autoantibody production was suppressed. Of note (MHC-II-independent) IgM were unaffected by Cat-S blockade while they were suppressed by MMF. Cat-S blockade dose-dependently suppressed immune-complex glomerulonephritis together with a profound and early effect on proteinuria, which was not shared by MMF. In fact, intravenous Cat-S injection induced severe glomerular endothelial injury and albuminuria, which was entirely prevented by Cat-S or PAR-2 blockade. In-vitro studies confirm that Cat-S induces endothelial activation and injury via PAR-2. Therapeutic Cat-S blockade suppresses systemic and peripheral pathomechanisms of autoimmune tissue injury, hence, Cat-S is a promising therapeutic target in lupus nephritis.

Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/β-thalassemic patients

“…22 Finally, an increase in the quantity of cathepsin S, a potent elastolytic protease, was detected in thalassemic EVs, which may originate from activated myeloid cells. 23 Only 2 proteins, hemopexin and haptoglobin, were consistently and significantly reduced (12.5-to 25-fold and 7.1-to 20-fold reduction, respectively) in the patient compared with control EV samples across the 3 experiments (Table 3). These data are consistent with the pathophysiology of thalassemia, with the hemolysis causing a dramatic decrease in these hemoglobin/heme scavengers.…”

“…Finally, we have also detected the altered levels of cathepsin S, a potent elastolytic protease that could be useful as an inflammatory plasma marker to monitor the degree of inflammation in thalassemia. 23 Future studies to evaluate the clinical application of these plasma biomarkers for monitoring the severity of thalassemia and transfusion requirements are now required.…”

Lysosomes as a therapeutic target

“…Cathepsins A and G are serine proteases, cathepsins D and E are aspartic proteases and cathep sins B, C, F, H, K, L, O, S, V, X and W are cysteine pro teases. For example, cathepsin S is responsible for the degradation of antigens (and autoantigens) in antigen presenting cells (dendritic cells, macrophages and B cells), and is therefore involved at an upstream level in the presentation of MHCII-(auto)antigenic peptide complexes to CD4 + T cells 81 . Cathepsin L preferentially cleaves peptide bonds with aromatic residues in the P2 position and hydrophobic residues in the P3 position.…”

Inflammation and host-pathogen interaction: Cause and consequence in cystic fibrosis lung disease

“…In paediatric patients with CF, CTSS was significantly increased in Pseudomonas-negative preschool children with CF compared to children without CF with recurrent respiratory infection, suggesting that this may be related to CFTR dysfunction [25]. Cellular sources of pulmonary CTSS include airway epithelial cells via dysregulated miR-31/IRF-1 signalling in CF epithelium [25], however macrophages and neutrophils [27,28] also represent potential sources in the CF lung.…”