Divergence of Macrophage Phagocytic and Antimicrobial Programs in Leprosy

Abstract

SUMMARY Effective innate immunity against many microbial pathogens requires macrophage programs that upregulate phagocytosis and direct antimicrobial pathways, two functions generally assumed to be coordinately regulated. Here the regulation of these key functions was investigated in human blood-derived macrophages. IL-10 induced the phagocytic pathway, including CD209 and scavenger receptors, resulting in phagocytosis of mycobacteria and oxLDL. IL-15 induced the vitamin D-dependent antimicrobial pathway and CD209, yet the cells were less phagocytic. The differential regulation of macrophage functional programs was confirmed by analysis of the spectrum of leprosy lesions: the macrophage phagocytosis pathway was prominent in the clinically progressive, multibacillary form, whereas the vitamin D-dependent antimicrobial pathway predominated in the self-limited form of the disease and in patients undergoing reversal reactions from the multibacillary to the self-limited form. These data indicate that macrophage programs for phagocytosis and antimicrobial responses are distinct and differentially regulated in innate immunity in bacterial infections.

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

“…Networks of genes involved in "endocytosis," "lysosome," and "phagosome" were identified and associated with macrophages, possibly reflecting the presence of IL-10-derived CD163 + M2 macrophages, which are programmed to be highly phagocytic (16,25). A lipid-binding pathway was present in L-lep lesions, which is consistent with the observation that host-derived lipids accumulate in macrophages in L-lep lesions (63).…”

“…As part of this network, other genes involved in "chemotaxis" and "tissue remodeling" included IRF6, ADIPOQ, OVOL1, and FOXQ1 (43)(44)(45)(46)(47)(48). Another prominent gene, CYP27B1, a member of the cytochrome p450 family, is a critical part of the vitamin D antimicrobial pathway to kill mycobacteria (16,25,49,50). Together, these networks link chemotaxis, tissue remodeling, and antimicrobial activity as part of the effective host response to limit mycobacterial infection.…”

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

“…Sulahian and colleagues [12,27] have demonstrated that IL-10 directly elevates CD163 mRNA. Since previous work has described the role of IL-10 in LL pathogenesis [10], we suggest that this cytokine is responsible for the maintenance of the heightened levels of CD163 in LL cells. It has also been shown that the IL-10 induction of scavenger and opsoninic receptors may facilitate antigen loading and initiate antigen presentation and adaptive immune responses to the infectious agent [28].…”

“…Foamy macrophages seem to sustain intracellular mycobacteria in a physiological state similar to a nonreplicating vegetative one [9]. In this context, Montoya et al [10] demonstrated that lepromatous macrophages exhibit a high expression of the cysteine-rich superfamily scavenger receptor (SRCR), which increases the phagocytic capacity of macrophages and leads to a reduction in bactericidal activity.…”

Haemophilus ducreyi-Induced Interleukin-10 Promotes a Mixed M1 and M2 Activation Program in Human Macrophages

“…However, M2 polarization is also associated with reduced host defense and chronic infection. For example, high levels of IL-10 and enrichment of other M2-associated gene expression profiles are found in lepromatous lesions in comparison to the tuberculoid lesions of Mycobacterium leprae infection (32). Chronic infection by several bacteria, such as Tropheryma whipplei, is associated with enhanced M2c polarization and suppressed M1 activation (12,33).…”