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

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

doi:10.3389/fcell.2020.00398

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.

Highlights

Among the different forms of renal replacement, therapy kidney transplantation, when available, is the preferred option for most patients with end-stage kidney disease (Wolfe et al, 1999; Robinson et al, 2016)
Cathepsin S–Positive Cells Accumulate in Rejecting Human Kidney Allografts
We found numerous CD68/cathepsin S (Cat-S) double-positive cells accumulating in rejected allografts (Figure 2B)

Summary

Introduction

Among the different forms of renal replacement, therapy kidney transplantation, when available, is the preferred option for most patients with end-stage kidney disease (Wolfe et al, 1999; Robinson et al, 2016). Within antigen-presenting cells, the maturation of MHC class II molecules is tightly regulated, whereby the invariant chain covers the peptide-binding domain up to when peptide loading occurs and the molecule is shuttled to the cell surface (Roche and Frusta, 2015; Robson et al, 2018). Cathepsin (Cat-) S is one of several proteases that chop the invariant chain in a stepwise process (Shi et al, 1999; Roche and Frusta, 2015); Cat-S deficiency or pharmaceutical Cat-S inhibition prevents MHC class II–mediated (auto)antigen presentation (Rise et al, 1996, 1998; Dresden et al, 1999; Saugus et al, 2002; Stickle et al, 2012). Cat-S inhibition effectively suppresses the immune dysregulation in numerous experimental autoimmune diseases (Saugus et al, 2002; Baugh et al, 2011; Rupanagudi et al, 2015; Tato et al, 2017)

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