Plasticity of antimicrobial and phagocytic programs in human macrophages

Abstract

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.

Liver Macrophages: Old Dogmas and New Insights

“…Indeed, it seems to be possible to re-educate macrophages from a classical so-called M1 to M2 phenotype and vice versa. (113) New technologies (sequencing techniques, imaging methods, unbiased big data analyses) allow for an exciting and fresh view on macrophage heterogeneity, for instance, regarding origin, polarization, localization in tissue, and function in relation to the disease state. (114) However, it is important to accurately describe the experimental setting from which conclusions are drawn to allow comparability between models and researchers.…”

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair

“…Macrophages are plastic populations and can display various functions simultaneously or in sequence. The possibility to reprogram or repolarize macrophages into different phenotypes and functions [36] holds great potential for targeting these cells for the treatment of liver diseases [11].…”

Macrophages in the Pathogenesis of Leprosy

“…In an anti-inflammatory profile (M2), this cell induces increased uptake of lipids [21,22] and Hb-haptoglobin [16,42], which aid the growth of M. leprae by the activation of the enzymes IDO [42,45], HO-1 [42] and arginase [37]. On the other hand, in a pro-inflammatory and microbicidal profile (M1), the macrophage produces TNF [26,48], IL-6 [37,48,49], and IL-15 [22,37,39] besides being able to stimulate T cells to produce IFN-γ [34]. In addition, these M1 macrophages induce autophagy [57,58], an important process of homeostatic regulation recently described with the immunological role [56], which acts on infection control.…”

“…Analysis of paucibacillary tuberculoid and reversal reaction (an acute inflammatory clinical condition associated with increased levels of IFN-γ in leprosy patients) patients' skin lesions demonstrated that macrophage subtypes with microbicidal and homeostatic functions are spatially distributed in tuberculoid granulomas according to the specific microenvironments [38]. The center of the tuberculoid granulomas appears to be populated by pro-inflammatory CD68 + CD163 − M1 macrophages, responsible for containing the infection, while the periphery is composed of anti-inflammatory CD68 + CD163 + M2 macrophages, tasked with limiting tissue damage caused by the M1 macrophage antimicrobial activity [39]. Accordingly, Montoya and colleagues [22] proposed two different macrophage functional programs for the polar clinical forms of leprosy.…”

“…They suggested that in tuberculoid paucibacillary patients, IL-15 induces the vitamin D-mediated antimicrobial program in the macrophages, resulting in killing of the mycobacteria, while in multibacillary lepromatous patients, the higher levels of IL-10 would induce the phagocytic pathway by increasing the expression of CD209 and scavenger receptors as CD163 in the macrophage cell surface, resulting in phagocytosis of M. leprae and oxidized low-density lipoproteins (LDL) favoring the formation of foam cells and persistence of the infection [22]. In addition, antimicrobial M1 macrophages differentiated with IL-15 could be repolarized into the phagocytic M2 phenotype after treatment with IL-10, while phagocytic IL-10-differentiated M2 macrophages could only be repolarized into the M1 phenotype after co-stimulation with TLR2/1 ligand and IFN-γ or TLR2/1 ligand and anti-IL-10-neutralizing antibodies, but not IL-15 or IFN-γ alone, suggesting that production IL-10 by M2 macrophages might create a barrier for M1 reprogramming [39].…”