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 extr...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Maia Tato, Santhosh V. Kumar, Yajuan Liu, Shrikant R. Mulay, Solange Moll, Bastian Popper, Jonathan N. Eberhard, Dana Thomasova, Arne Christian Rufer, Sabine Gruner, Wolfgang Haap, Guido Hartmann, Hans-Joachim Anders
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/12a6dc699d414a39ba47ee1d44e92198
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:12a6dc699d414a39ba47ee1d44e92198
record_format	dspace
spelling	oai:doaj.org-article:12a6dc699d414a39ba47ee1d44e921982021-12-02T12:32:40ZCathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury10.1038/s41598-017-01894-y2045-2322https://doaj.org/article/12a6dc699d414a39ba47ee1d44e921982017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01894-yhttps://doaj.org/toc/2045-2322Abstract 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.Maia TatoSanthosh V. KumarYajuan LiuShrikant R. MulaySolange MollBastian PopperJonathan N. EberhardDana ThomasovaArne Christian RuferSabine GrunerWolfgang HaapGuido HartmannHans-Joachim AndersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maia Tato Santhosh V. Kumar Yajuan Liu Shrikant R. Mulay Solange Moll Bastian Popper Jonathan N. Eberhard Dana Thomasova Arne Christian Rufer Sabine Gruner Wolfgang Haap Guido Hartmann Hans-Joachim Anders Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
description	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.
format	article
author	Maia Tato Santhosh V. Kumar Yajuan Liu Shrikant R. Mulay Solange Moll Bastian Popper Jonathan N. Eberhard Dana Thomasova Arne Christian Rufer Sabine Gruner Wolfgang Haap Guido Hartmann Hans-Joachim Anders
author_facet	Maia Tato Santhosh V. Kumar Yajuan Liu Shrikant R. Mulay Solange Moll Bastian Popper Jonathan N. Eberhard Dana Thomasova Arne Christian Rufer Sabine Gruner Wolfgang Haap Guido Hartmann Hans-Joachim Anders
author_sort	Maia Tato
title	Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
title_short	Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
title_full	Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
title_fullStr	Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
title_full_unstemmed	Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
title_sort	cathepsin s inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/12a6dc699d414a39ba47ee1d44e92198
work_keys_str_mv	AT maiatato cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT santhoshvkumar cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT yajuanliu cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT shrikantrmulay cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT solangemoll cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT bastianpopper cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT jonathanneberhard cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT danathomasova cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT arnechristianrufer cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT sabinegruner cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT wolfganghaap cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT guidohartmann cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury AT hansjoachimanders cathepsinsinhibitioncombinescontrolofsystemicandperipheralpathomechanismsofautoimmunetissueinjury
_version_	1718393961724248064

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

Ejemplares similares