Plasticity of antimicrobial and phagocytic programs in human macrophages |
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Authors: | Dennis Montoya Manali Mehta Benjamin G. Ferguson Rosane M. B. Teles Stephan R. Krutzik Daniel Cruz Matteo Pellegrini Robert L. Modlin |
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Affiliation: | 1. Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA, USA;2. Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA;3. Department of Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA;4. Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA |
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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 (M1 MΦ) have enhanced antimicrobial activity, whereas IL-10-derived alternatively activated macrophages (M2 MΦ) were highly phagocytic but lacked antimicrobial activity. Given that the ability to modulate MΦ polarization from M2 MΦ to M1 MΦ may promote a more effective immune response to infection, we investigated the plasticity of these MΦ programs. Addition of IL-10 to M1 MΦ induced M2-like MΦ, but IL-15 had little effect on M2 MΦ. We determined the set of immune receptors that are present on M2 MΦ, elucidating two candidates for inducing plasticity of M2 MΦ, Toll-like receptor 1 (TLR1) and interferonγ (IFN-γ) receptor 1. Stimulation of M2 MΦ with TLR2/1 ligand (TLR2/1L) or IFN-γ alone was not sufficient to alter M2 MΦ phenotype or function. However, co-addition of TLR2/1L and IFN-γ re-educated M2 MΦ towards the M1 MΦ 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 MΦ maintained in polarizing conditions. Similarly, treatment of M2 MΦ 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. |
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Keywords: | antimicrobial macrophage mycobacteria phagocytosis polarization |
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