title: Soluble CD163 masks fibronectin-binding protein A-mediated inflammatory activation of Staphylococcus aureus infected monocytes.
abstract: Binding to fibronectin (FN) is a crucial pathogenic factor of Staphylococcus aureus mediated by fibronectin-binding protein A (FnBP-A) and extracellular adherence protein (Eap). Recently, we have shown that binding of soluble CD163 (sCD163) to FN linked to these molecules exhibits anti-microbial effects by enhancing phagocytosis and killing activity of S. aureus-infected monocytes. However, it remained unclear whether sCD163 also influences the monocytic activation status. Using genetically modified staphylococcal strains we now identified FnBP-A, but not Eap, as activator of the inflammatory response of monocytes to infection. FnBP-A-mediated inflammatory activation was masked by sCD163 binding to S. aureus promoting efficient pathogen elimination. Thus, sCD163 protects monocytes from overwhelming activation upon staphylococcal infection by dampening the secretion of pro-inflammatory cytokines TNFα, IL-1β, IL-6 and IL-8 and DAMP molecule MRP8/14. Moreover, sCD163 limited expression of pro-apoptotic transcription factor NR4A1 induced during S. aureus infection and inhibited induction of chemokine CXCL2promoting survival of staphylococci in vivo. sCD163-mediated effects were not due to general immunosuppression since MAP kinase activation and ROS production were unaltered during infection of monocytes with sCD163-bound bacteria. Thus, sCD163 promotes a specific defence of the immune system against FnBP-A-mediated inflammatory activation enabling successful pathogen elimination, tissue recovery and resolution of inflammation.
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research, University of Muenster, Muenster, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kneidl
authors.forename: Vijayashree
authors.initials: V
authors.lastname: Mysore
authors.forename: Jennifer
authors.initials: J
authors.lastname: Geraci
authors.forename: Lorena
authors.initials: L
authors.lastname: Tuchscherr
authors.forename: Bettina
authors.initials: B
authors.lastname: Löffler
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Barczyk-Kahlert
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000378:metabolism; D018829:Adhesins, Bacterial / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D040502:Calgranulin B / Q000096:biosynthesis; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis; D010587:Phagocytosis / Q000276:immunology; D016601:RNA-Binding Proteins / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D013203:Staphylococcal Infections / Q000276:immunology; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D018829:Adhesins, Bacterial; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001426:Bacterial Proteins; D000098902:CD163 Antigen; C499706:CXCL2 protein, human; C508606:CXCL8 protein, human; D040502:Calgranulin B; D054426:Chemokine CXCL2; C444739:Eap-N protein, Staphylococcus aureus; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C078635:fibronectin-binding proteins, bacterial; D020928:Mitogen-Activated Protein Kinases