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Title

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

Authors
Tato, Maia
Kumar, Santhosh V
Liu, Yajuan
Mulay, Shrikant R
Popper, Bastian
Eberhard, Jonathan N
Thomasova, Dana
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Published in Scientific Reports. 2017, vol. 7, no. 1, p. 2775
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.
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PMID: 28584258
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Article (Published version) (2.9 MB) - public document Free access
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Research group Analyse protéomique et Analyse génomique des maladies rénales (659)
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TATO, Maia et al. Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. In: Scientific Reports, 2017, vol. 7, n° 1, p. 2775. https://archive-ouverte.unige.ch/unige:98390

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Deposited on : 2017-11-01

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