Published online before print December 5, 2005

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(Journal of Leukocyte Biology. 2006;79:285-293.)
© 2006 by Society for Leukocyte Biology

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

Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, the Netherlands

²Correspondence: Department of IHB, LUMC, Albinusdreef 2, Leiden NL-2333-ZA, the Netherlands. E-mail: t.h.m.ottenhoff{at}lumc.nl

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- (IFN-) and CD40L as costimulatory T cell back-talk signals. Activated IL-23⁺/IL-12⁺ M-1 secreted IL-1ß, 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-1ß (MIP-1ß), 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-1ß, IL-6, TNF-, MDC, or TARC. It is remarkable that M-2 secreted high levels of IL-8, MCP-1, IP-10, MIP-1ß, 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.

Key Words: macrophage polarization • proinflammatory cyto-kines • chemokines • mycobacteria • immune escape

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