Plasticity of antimicrobial and phagocytic programs in human macrophages

Summary 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 antim...

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Bibliographic Details
Published in:Immunology 2019-02, Vol.156 (2), p.164-173
Main Authors: Montoya, Dennis, Mehta, Manali, Ferguson, Benjamin G., Teles, Rosane M. B., Krutzik, Stephan R., Cruz, Daniel, Pellegrini, Matteo, Modlin, Robert L.
Format: Article
Language:English
Subjects:
Antibodies
Antiinfectives and antibacterials
antimicrobial
Antimicrobial activity
Antimicrobial agents
Cytokines - immunology
Disease control
Female
Genotype & phenotype
Humans
Immune response
Immune system
Innate immunity
Interferon
Interferon gamma Receptor
Interleukins
Lipids
macrophage
Macrophage Activation
Macrophages
Macrophages - immunology
Macrophages - pathology
Male
Microorganisms
mycobacteria
Mycobacterium Infections - immunology
Mycobacterium Infections - pathology
Original
Pathogenesis
Pathogens
Phagocytes
Phagocytosis
Phenotypes
Plastic properties
Plasticity
Polarization
Receptors
Receptors, Interferon - immunology
TLR1 protein
TLR2 protein
Toll-Like Receptor 1 - immunology
Toll-Like Receptor 2 - immunology
Toll-like receptors
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Summary:Summary 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. We investigate the mechanisms by which IL‐15 versus IL‐10 polarized MΦ are re‐educated in an effort to understand MΦ plasticity in diseases in which MΦ contribute to pathogenesis. We demonstrate that the re‐education of M2 MΦ into M1‐like MΦ by co‐addition of TLR2/1L and IFN‐γ led to up‐regulation of key components of the vitamin D antimicrobial pathway and down‐regulation of phagocytic activity. Together, our data demonstrate an approach to induce MF plasticity that provides the potential for re‐educating MF function in human mycobacterial disease to promote host defense and limit pathogenesis.
ISSN:0019-2805
1365-2567
DOI:10.1111/imm.13013