Plasticity of antimicrobial and phagocytic programs in human macrophages

Summary Macrophage (M Φ ) polarization is triggered during the innate immune response to defend against microbial pathogens, but can also contribute to disease pathogenesis. In a previous study, we found that interleukin‐15 (IL‐15) ‐derived classically activated macrophages (M1 M Φ ) have enhanced antimicrobial activity, whereas IL‐10‐derived alternatively activated macrophages (M2 M Φ ) were highly phagocytic but lacked antimicrobial activity. Given that the ability to modulate M Φ polarization from M2 M Φ to M1 M Φ may promote a more effective immune response to infection, we investigated the plasticity of these M Φ programs. Addition of IL‐10 to M1 M Φ induced M2‐like M Φ , but IL‐15 had little effect on M2 M Φ . We determined the set of immune receptors that are present on M2 M Φ , elucidating two candidates for inducing plasticity of M2 M Φ , Toll‐like receptor 1 (TLR1) and interferon γ (IFN‐ γ ) receptor 1. Stimulation of M2 M Φ with TLR2/1 ligand (TLR2/1L) or IFN‐ γ alone was not sufficient to alter M2 M Φ phenotype or function. However, co‐addition of TLR2/1L and IFN‐ γ re‐educated M2 M Φ towards the M1 M Φ phenotype, with a decrease in the phagocytosis of lipids and mycobacteria, as well as recovery of the vitamin‐D‐dependent antimicrobial pathway compared with M2 M Φ maintained in polarizing conditions. Similarly, treatment of M2 M Φ with both TLR2/1L and anti‐IL‐10 neutralizing antibodies led to polarization to the M1‐like M Φ phenotype and function. Together, our data demonstrate an approach to induce M Φ plasticity that provides the potential for re‐educating M Φ function in human mycobacterial disease to promote host defense and limit pathogenesis.