Symbiotic gut commensal bacteria act as host cathepsin S activity regulators

Alex Steimle, Kerstin Gronbach, Brigitte Beifuss, Andrea Schäfer, Robin Harmening, Annika Bender, Jan Kevin Maerz, Anna Lange, Lena Michaelis, Andreas Maurer, Sarah Menz, Kathy McCoy, Ingo B. Autenrieth, Hubert Kalbacher, Julia Stefanie Frick*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Abstract

Cathepsin S (CTSS) is a lysosomal protease whose activity regulation is important for MHC-II signaling and subsequent activation of CD4+ T cell mediated immune responses. Dysregulation of its enzymatic activity or enhanced secretion into extracellular environments is associated with the induction or progression of several autoimmune diseases. Here we demonstrate that commensal intestinal bacteria influence secretion rates and intracellular activity of host CTSS and that symbiotic bacteria, i.e. Bacteroides vulgatus mpk, may actively regulate this process and help to maintain physiological levels of CTSS activities in order to prevent from induction of pathological inflammation. The symbiont-controlled regulation of CTSS activity is mediated by anticipating reactive oxygen species induction in dendritic cells which, in turn, maintains cystatin C (CysC) monomer binding to CTSS. CysC monomers are potent endogenous CTSS inhibitors. This Bacteroides vulgatus caused and CysC dependent CTSS activity regulation is involved in the generation of tolerant intestinal dendritic cells contributing to prevention of T-cell mediated induction of colonic inflammation. Taken together, we demonstrate that symbionts of the intestinal microbiota regulate host CTSS activity and secretion and might therefore be an attractive approach to deal with CTSS associated autoimmune diseases.

Original languageEnglish
Pages (from-to)82-95
Number of pages14
JournalJournal of Autoimmunity
Volume75
DOIs
Publication statusPublished - 1 Dec 2016
Externally publishedYes

Keywords

  • Autoimmune disease
  • Cathepsin S
  • Immunotherapy
  • Inflammatory bowel disease
  • Microbiota
  • Protease regulation

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