Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
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Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. / Tato, Maia; Kumar, Santhosh V; Liu, Yajuan; Mulay, Shrikant R; Moll, Solange; Popper, Bastian; Eberhard, Jonathan N; Thomasova, Dana; Rufer, Arne Christian; Gruner, Sabine; Haap, Wolfgang; Hartmann, Guido; Anders, Hans-Joachim.
In: SCI REP-UK, Vol. 7, No. 1, 05.06.2017, p. 2775.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
AU - Tato, Maia
AU - Kumar, Santhosh V
AU - Liu, Yajuan
AU - Mulay, Shrikant R
AU - Moll, Solange
AU - Popper, Bastian
AU - Eberhard, Jonathan N
AU - Thomasova, Dana
AU - Rufer, Arne Christian
AU - Gruner, Sabine
AU - Haap, Wolfgang
AU - Hartmann, Guido
AU - Anders, Hans-Joachim
PY - 2017/6/5
Y1 - 2017/6/5
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1038/s41598-017-01894-y
DO - 10.1038/s41598-017-01894-y
M3 - SCORING: Journal article
C2 - 28584258
VL - 7
SP - 2775
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -