title: Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria.
abstract: Macrophages (Mphi) play a central role as effector cells in immunity to intracellular pathogens such as Mycobacterium. Paradoxically, they also provide a habitat for intracellular bacterial survival. This paradoxical role of Mphi remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mphi: Whereas Mphi-1 polarized in the presence of granulocyte-Mphi colony-stimulating factor promoted type 1 immunity, Mphi-2 polarized with Mphi colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mphi-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated Mphi-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mphi-1 required IFN-gamma as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion. Activated dendritic cells produced both IL-12 and IL-23, but unlike Mphi-1 they slightly reduced their IL-23 secretion after addition of IFN-gamma. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mphi subsets, but more efficiently by Mphi-2 than Mphi-1. Whereas Mphi-1 efficiently stimulated type 1 helper cells, Mphi-2 only poorly supported type 1 helper function. Accordingly, activated Mphi-2 but not Mphi-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mphi-1 and Mphi-2 play opposing roles in cellular immunity and (ii) IL-23 rather than IL-12 is the primary type 1 cytokine produced by activated proinflammatory Mphi-1. Mphi heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Albinusdreef 2, NL-2333-ZA, Leiden, The Netherlands. verreck@bprc.nl
authors.forename: Frank A W
authors.initials: FA
authors.lastname: Verreck
authors.forename: Tjitske
authors.initials: T
authors.lastname: de Boer
authors.forename: Dennis M L
authors.initials: DM
authors.lastname: Langenberg
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Hoeve
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kramer
authors.forename: Elena
authors.initials: E
authors.lastname: Vaisberg
authors.forename: Robert
authors.initials: R
authors.lastname: Kastelein
authors.forename: Arend
authors.initials: A
authors.lastname: Kolk
authors.forename: René
authors.initials: R
authors.lastname: de Waal-Malefyt
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D009000:Monocytes / Q000166:cytology; D009161:Mycobacterium / Q000254:growth & development / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D018793:Interleukin-13; D016753:Interleukin-10