Abstract
Tuberculosis, a human infectious disease caused by Mycobacterium tuberculosis (M.tb), is still a major cause of morbidity and mortality worldwide. The success of M.tb as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which M.tb maintains a persistent infection in a “silent” granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However, M.tb effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The Early Secreted Antigenic Target 6 kDa or ESAT-6, has been implicated in the virulence and pathogenesis of tuberculosis. Here, we investigated roles of ESAT-6 in MΦ differentiation and polarization. We found that treatment of human monocytes with ESAT-6 did not interfere with differentiation of M1 MΦs. However, ESAT-6 promoted differentiation of M0 and M2 MΦs toward the M1 phenotype, as indicated by secretion of pro-inflammatory cytokines IL-6, IL-12, and TNF-α, and induction of a typical M1 transcriptional signature. Interestingly, we found that ESAT-6 switched terminal full activation of M1 polarized MΦs to the M2 phenotype. Indeed, in the pro-inflammatory M1 MΦs, ESAT-6 was able to inhibit IL-12 and TNF-α secretion and stimulate that of IL-10. Moreover, gene expression profiling of these cells showed that ESAT-6 induced downregulation of M1 MΦ cell surface molecules CD80 and CD86, transcription factors IRF5 and c-MAF, cytokines IL-12, IL-10, and IL-6, as well as chemokines CXCL10 and CXCL1. Overall, our findings suggest ESAT-6 as being one of the effectors used by M.tb to induce the pro-inflammatory M1 phenotype at the primo-infection; a prerequisite step to promote granuloma formation and subsequently drive the phenotype switch of MΦ polarization from M1 to M2 at a later stage of the infection. Our study improves current knowledge regarding mechanisms of virulence of M.tb and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.
Highlights
Tuberculosis, due to infection with M.tb, is a leading infectious disease and one of the major causes of death worldwide
When ESAT-6 is not present in medium, we found that M0 MΦs secreted low amounts of IL-10, IL-6, IL-12, and TNFα, while GM-CSF- or M-CSF-induced monocyte differentiation into M1 or M2 MΦs, respectively, yielded moderate levels of the studied cytokines (Figures 2A–D)
The cytokine profile showed that M1 MΦs secreted significantly higher amounts of IL-6 (p = 0.005, Figure 2B), IL-12 (p = 0.046, Figure 2C) and TNF-α (p = 0.048, Figure 2D) than M0 MΦs, whereas almost no pro-inflammatory cytokines were secreted by M2 MΦs (Figures 2B–D)
Summary
Tuberculosis, due to infection with M.tb, is a leading infectious disease and one of the major causes of death worldwide. Alternatively activated M2 MΦs are defined by low production of pro-inflammatory cytokines IL12 and IL-23 and high production of the anti-inflammatory cytokine IL-10 (Martinez and Gordon, 2014; Murray et al, 2014; Wang et al, 2014; Sica et al, 2015; Murray, 2017) These cells show more phagocytic activity, higher expression of mannose and galactose receptors and scavenging molecules, as well as higher production of ornithine and polyamines (Mantovani et al, 2004; Sica and Mantovani, 2012). A switch between pro- and anti-inflammatory cytokine profiles is seen during this phenotypic reversibility (Muller and Tjardes, 2003)
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