Cathepsin S and Protease-Activated Receptor-2 Drive Alloimmunity and Immune Regulation in Kidney Allograft Rejection

Yutian Lei, Benjamin Ehle, Santhosh V. Kumar, Susanne Müller, Solange Moll, Andrew F. Malone, Benjamin D. Humphreys, Joachim Andrassy, Hans Joachim Anders

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Alloantigen presentation is an essential process in acute allorejection. In this context, we speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to promote antigenic peptide loading into MHC class II and to activate protease-activated receptor (PAR)-2 on intrarenal microvascular endothelial and tubular epithelial cells. Single-cell RNA sequencing and immunostaining of human kidney allografts confirmed Cat-S expression in intrarenal mononuclear phagocytes. In vitro, Cat-S inhibition suppressed CD4 + T cell lymphocyte activation in a mixed lymphocyte assay. In vivo, we employed a mouse model of kidney transplantation that showed preemptive Cat-S inhibition significantly protected allografts from tubulitis and intimal arteritis. To determine the contribution of PAR-2 activation, first, Balb/c donor kidneys were transplanted into Balb/c recipient mice without signs of rejection at day 10. In contrast, kidneys from C57BL/6J donor mice revealed severe intimal arteritis, tubulitis, interstitial inflammation, and glomerulitis. Kidneys from Par2-deficient C57BL/6J mice revealed partial protection from tubulitis and lower intrarenal expression levels for Fasl, Tnfa, Ccl5, and Ccr5. Together, we conclude that Cat-S and PAR-2 contribute to immune dysregulation and kidney allograft rejection, possibly involving Cat-S-mediated activation of PAR-2 on recipient parenchymal cells in the allograft.

Original languageEnglish
Article number398
JournalFrontiers in Cell and Developmental Biology
Volume8
DOIs
StatePublished - Jun 5 2020

Keywords

  • allorejection
  • animal model of transplantation
  • cathepsin S
  • kidney transplantation
  • proteinase-activated receptor-2

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