Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-?3- and CD40L-mediated costimulation

摘要

Macrophages (M??) comprise a heterogeneous population of cells with various immune and homeostatic functions. Recently, we have described type-1 and type-2 human monocyte-derived M?? subsets. Although both support outgrowth of intracellular mycobacteria, M??-1 secretes interleukin (IL)-23/IL-12 and supports T helper cell type 1 (Th1) responses, whereas M??-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 M??-1 and M??-2 in response to microbial antigens and interferon-?3 (IFN-?3) and CD40L as costimulatory T cell back-talk signals. Activated IL-23+/IL-12+ M??-1 secreted IL-1?2, IL-18, IL-6, and tumor necrosis factor-?± (TNF-?±), as well as IL-8, monocyte chemoattractant protein-1 (MCP-1), IFN-inducible protein 10 (IP-10), M?? inflammatory protein-1?2 (MIP-1?2), regulated on activation, normal T expressed and secreted (RANTES), M??-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, M??-2 maintained their IL-10+ signature cytokine profile and produced no or relatively low levels of IL-12p40, IL-1?2, IL-6, TNF-?±, MDC, or TARC. It is remarkable that M??-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1?2, and RANTES, suggesting an active role for these cells in regulating cellular immunity and homeostasis. M??-1 and M??-2 expressed similar levels of Toll-like receptor and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as microbial pattern recognition receptors. M??-2, unlike M??-1 but like other nonclassical M?? described previously, expressed CD163 and down-modulated human leukocyte antigen and costimulatory molecules specifically upon activation. These findings demonstrate how M??-1/M??-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.