title: Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-gamma- and CD40L-mediated costimulation.
abstract: Macrophages (Mphi) comprise a heterogeneous population of cells with various immune and homeostatic functions. Recently, we have described type-1 and type-2 human monocyte-derived Mphi subsets. Although both support outgrowth of intracellular mycobacteria, Mphi-1 secretes interleukin (IL)-23/IL-12 and supports T helper cell type 1 (Th1) responses, whereas Mphi-2 fails to produce IL-23/IL-12, predominantly secretes IL-10, and inhibits Th1 function. Here, we further describe the phenotypic and functional profiles of Mphi-1 and Mphi-2 in response to microbial antigens and interferon-gamma (IFN-gamma) and CD40L as costimulatory T cell back-talk signals. Activated IL-23(+)/IL-12(+) Mphi-1 secreted IL-1beta, IL-18, IL-6, and tumor necrosis factor-alpha (TNF-alpha), as well as IL-8, monocyte chemoattractant protein-1 (MCP-1), IFN-inducible protein 10 (IP-10), Mphi inflammatory protein-1beta (MIP-1beta), regulated on activation, normal T expressed and secreted (RANTES), Mphi-derived chemokine (MDC), and (low levels of) pulmonary and activation-regulated chemokine and thymus and activation-regulated chemokine (TARC), corroborating their proinflammatory function. Regardless of the stimulus, Mphi-2 maintained their IL-10(+) signature cytokine profile and produced no or relatively low levels of IL-12p40, IL-1beta, IL-6, TNF-alpha, MDC, or TARC. It is remarkable that Mphi-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1beta, and RANTES, suggesting an active role for these cells in regulating cellular immunity and homeostasis. Mphi-1 and Mphi-2 expressed similar levels of Toll-like receptor and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as microbial pattern recognition receptors. Mphi-2, unlike Mphi-1 but like other nonclassical Mphi described previously, expressed CD163 and down-modulated human leukocyte antigen and costimulatory molecules specifically upon activation. These findings demonstrate how Mphi-1/Mphi-2 polarization can differentially skew the host response toward pro- or anti-inflammatory immune responses, respectively. This is likely to be relevant for host-pathogen interactions in chronic bacterial infections and provides a model for dissecting pro- and anti-inflammatory cascades.
authors.affiliation: LUMC, Albinusdreef 2, Leiden NL-2333-ZA, The Netherlands.
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: Linda
authors.initials: L
authors.lastname: van der Zanden
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000942:Antigens, Bacterial / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D023201:CD40 Ligand / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000494:pharmacology*; D007378:Interleukins / Q000378:metabolism; D008264:Macrophages / Q000145:classification* / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D015415:Biomarkers; D018925:Chemokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma