Plasticity of antimicrobial and phagocytic programs in human macrophages.

Abstract

Macrophage (MΦ) 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 (M1MΦ) have enhanced antimicrobial activity, whereas IL-10-derived alternatively activated macrophages (M2MΦ) were highly phagocytic but lacked antimicrobial activity. Given that the ability to modulate MΦ polarization from M2MΦ to M1MΦ may promote a more effective immune response to infection, we investigated the plasticity of these MΦ programs. Addition of IL-10 to M1MΦ induced M2-like MΦ, but IL-15 had little effect on M2MΦ. We determined the set of immune receptors that are present on M2MΦ, elucidating two candidates for inducing plasticity of M2MΦ, Toll-like receptor 1 (TLR1) and interferonγ (IFN-γ) receptor 1. Stimulation of M2MΦ with TLR2/1 ligand (TLR2/1L) or IFN-γ alone was not sufficient to alter M2MΦ phenotype or function. However, co-addition of TLR2/1L and IFN-γ re-educated M2MΦ towards the M1MΦ phenotype, with a decrease in the phagocytosis of lipids and mycobacteria, as well as recovery of the vitamin-D-dependent antimicrobial pathway compared with M2MΦ maintained in polarizing conditions. Similarly, treatment of M2MΦ with both TLR2/1L and anti-IL-10 neutralizing antibodies led to polarization to the M1-like MΦ phenotype and function. Together, our data demonstrate an approach to induce MΦ plasticity that provides the potential for re-educating MΦ function in human mycobacterial disease to promote host defense and limit pathogenesis.