Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.

Multi-OMICs analysis reveals metabolic and epigenetic changes associated with macrophage polarization

“…Figure 2 D illustrates a heat map of protein expression in M1- and M2-MФs compared to M0-MФs and between M1- and M2-MФs. Among the 10 most upregulated proteins, LGALS3/Galectin 3 was elevated in M1-MФs, consistent with our previous RNA-seq analysis ( 47 ). LGALS3 is associated with autophagy-dependent antibacterial activity ( 48 ).…”

Reinventing the human tuberculosis (TB) granuloma: Learning from the cancer field

“…Mtb-infected macrophages or tumor-associated macrophages (TAMs) derive from both tissue-resident cells and from peripheral blood monocytes that are recruited to the disease site in response to inflammation ( 27 ). Th1 cytokines including IFN-γ, promote polarization of classically activated M1 macrophages that secrete pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α and have potent antigen processing and presenting abilities as well as cytotoxic and antimicrobial activities and are considered anti-tumorigenic ( 28 , 29 ). Proinflammatory M1 macrophages are capable of killing Mtb-infected cells or tumor cells via release of lysosomal enzymes, reactive nitrogen intermediates (RNI) and reactive oxygen species (ROS).…”

Cross center single-cell RNA sequencing study of the immune microenvironment in rapid progressing multiple myeloma

“…Markers to identify cell types were derived from a variety of sources. A supplementary table with the markers used for annotation is available (Supplementary Table 4) 25,[53][54][55][56][57][58][59] .…”