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

Maia Tato,Hans-Joachim Anders,Sabine Gruner,Santhosh V Kumar,Arne Christian Rufer,Wolfgang Haap,Yajuan Liu,Guido Hartmann,Shrikant R Mulay,Jonathan N Eberhard,Bastian Popper,Dana Thomasova,Solange Moll

doi:10.1038/s41598-017-01894-y

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.

Highlights

Cathepsin(Cat)-S processing of the invariant chain-major histocompatibility complex (MHC)-II complex inside antigen presenting cells is a central pathomechanism of autoimmune-diseases
The essential roles of Cat-S in MHC-II processing and in protease-activated receptor (PAR)-2-mediated vascular injury prompted us to speculate that therapeutic Cat-S inhibition could elicit a dual effect on autoimmune vascular disease that is more selective and superior to conventional immunosuppressive drugs. Our data validate this concept for RO5459072-mediated Cat-S inhibition in lupus nephritis of MRL-(Fas)lpr mice
Selective Cat-S inhibition avoids the unspecific immunosuppressive effect of mycophenolate mofetil (MMF) on plasma IgM that are important for first line host defense

Summary

Introduction

Cathepsin(Cat)-S processing of the invariant chain-MHC-II complex inside antigen presenting cells is a central pathomechanism of autoimmune-diseases. Specific targeting of immune processes has become possible with biological drugs, some of which have proven to be extremely efficent in controling autoimmune diseases such as anti-TNF-α in rheumatoid arthritis and Crohn’s disease or anti-CD20 in rheumatoid arthritis and ANCA vasculitis These drugs are less effective in other forms of systemic autoimmunity[3, 4], probably because they may not target universal pathomechanisms of autoimmunity. We hypothesized that Cat-S inhibition may have a dual therapeutic effect on vascular autoimmune tissue injury, i.e. suppression of MHC-II-dependent systemic autoimmunity as well as peripheral tissue protection from autoimmune vascular injury To address this concept we developed a novel highly-specific Cat-S inhibitor and tested it in vivo in comparison to standard immunosuppression in a model of lupus-like immune complex-related vasculopathy of the kidney, i.e. lupus nephritis

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Conclusion