title: S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes.
abstract: Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N-acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10- and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC-associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment.
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Judith Luiza
authors.initials: JL
authors.lastname: Eisenbacher
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Wuerttemberg-Hessen, 89081 Ulm, Germany; and.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.affiliation: Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Wuerttemberg-Hessen, 89081 Ulm, Germany; and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jahrsdörfer
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Christof
authors.initials: C
authors.lastname: Kaltenmeier
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Markus Thomas
authors.initials: MT
authors.lastname: Rojewski
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Yildiz
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Thamara
authors.initials: T
authors.lastname: Beyer
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Erle
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Denis Sebastian
authors.initials: DS
authors.lastname: Wiegmann
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Grassl
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;
authors.forename: Regina
authors.initials: R
authors.lastname: Hang
authors.affiliation: Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Wuerttemberg-Hessen, 89081 Ulm, Germany; and.
authors.forename: Sixten
authors.initials: S
authors.lastname: Körper
authors.affiliation: Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Wuerttemberg-Hessen, 89081 Ulm, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Wiesneth
authors.affiliation: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Wuerttemberg-Hessen, 89081 Ulm, Germany; and r.lotfi@blutspende.de.
authors.forename: Ramin
authors.initials: R
authors.lastname: Lotfi
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000819:agonists / Q000494:pharmacology*; D014527:Uric Acid / Q000819:agonists / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; C508609:IL10 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D016753:Interleukin-10; C077591:S100A4 protein, human; D014527:Uric Acid