title: Symbiotic gut commensal bacteria act as host cathepsin S activity regulators.
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.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Alex
authors.initials: A
authors.lastname: Steimle
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gronbach
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Beifuss
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Harmening
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Bender
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Jan Kevin
authors.initials: JK
authors.lastname: Maerz
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Lange
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Michaelis
authors.affiliation: Institute of Radiology, Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Maurer
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Menz
authors.affiliation: Department of Clinical Reasearch, Gastroenterology, University of Bern, Bern, Switzerland.
authors.forename: Kathy
authors.initials: K
authors.lastname: McCoy
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany.
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Autenrieth
authors.affiliation: Interfacultary Institute of Biochemistry, Universitiy of Tübingen, Tübingen, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany. Electronic address: julia-stefanie.frick@med.uni-tuebingen.de.
authors.forename: Julia-Stefanie
authors.initials: JS
authors.lastname: Frick
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology*; D001439:Bacteroides / Q000276:immunology / Q000502:physiology; D001442:Bacteroides Infections / Q000276:immunology / Q000382:microbiology; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002219:Carbamates / Q000494:pharmacology; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000276:immunology* / Q000502:physiology; D015870:Gene Expression / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013559:Symbiosis / Q000276:immunology*
chemical_list: D001578:Benzopyrans; D002219:Carbamates; D016207:Cytokines; C000601502:LY3000328; D017382:Reactive Oxygen Species; D002403:Cathepsins; C028217:cathepsin S
keywords: Autoimmune disease; Cathepsin S; Immunotherapy; Inflammatory bowel disease; Microbiota; Protease regulation