Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria

Abstract

Macrophages (Mψ) 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 Mψ remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of Mψ Whereas Mψ-1 polarized in the presence of granulocyte-Mψ colony-stimulating factor promoted type 1 immunity, Mψ-2 polarized with Mψ colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, Mψ-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated Mψ-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. Mψ-1 required IFN-γ, 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 Mψ-1 they slightly reduced their IL-23 secretion after addition of IFN-γ. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both Mψ subsets, but more efficiently by Mψ-2 than Mψ-1. Whereas Mψ-1 efficiently stimulated type 1 helper cells, Mψ-2 only poorly supported type 1 helper function. Accordingly, activated Mψ-2 but not Mψ-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i) Mψ-1 and Mψ-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 Mψ-1. Mψ heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.