Abstract
The tuberculous granuloma is an elaborately organized structure and one of the main histological hallmarks of tuberculosis. Macrophages, which are important immunologic effector and antigen-presenting cells, are the main cell type found in the tuberculous granuloma and have high plasticity. Macrophage polarization during bacterial infection has been elucidated in numerous recent studies; however, macrophage polarization during tuberculous granuloma formation and development has rarely been reported. It remains to be clarified whether differences in the activation status of macrophages affect granuloma formation. In this study, the variation in macrophage polarization during the formation and development of tuberculous granulomas was investigated in both sections of lung tissues from tuberculosis patients and an in vitro tuberculous granuloma model. The roles of macrophage polarization in this process were also investigated. Mycobacterium tuberculosis (M. tuberculosis) infection was found to induce monocyte-derived macrophage polarization. In the in vitro tuberculous granuloma model, macrophage transformation from M1 to M2 was observed over time following M. tuberculosis infection. M2 macrophages were found to predominate in both necrotic and non-necrotic granulomas from tuberculosis patients, while both M1 and M2 polarized macrophages were found in the non-granulomatous lung tissues. Furthermore, it was found that M1 macrophages promote granuloma formation and macrophage bactericidal activity in vitro, while M2 macrophages inhibit these effects. The findings of this study provide insights into the mechanism by which M. tuberculosis circumvents the host immune system as well as a theoretical foundation for the development of novel tuberculosis therapies based on reprogramming macrophage polarization.
Highlights
Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the major causes of mortality worldwide and is responsible for 1–2 million deaths each year [1, 2]
Before the exploration of macrophage polarization during the course of M.tuberculosis infection, we first determined the phenotypic and functional markers associated with human M1 and M2 macrophages, including CD86, CD163, CD206, HLA-DR, CXCL10, CXCL11, CCR7, CCL17, and CCL18, as well as the expression of related cytokines in the culture supernatant, including IL-6, IL-10, IL-12, and TNF-α
Increasing evidence has shown that macrophages play a dual role in M. tuberculosis infection
Summary
Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the major causes of mortality worldwide and is responsible for 1–2 million deaths each year [1, 2]. 5%–10% of infected individuals develop clinical symptoms, indicating that the host immune system constrains M. tuberculosis replication in all other infected individuals. It has been reported that the development and prognosis of tuberculous granulomas determine the outcome in M. tuberculosis infections to some extent [4,5,6], the details of this function remain unclear. Following the phagocytosis of M. tuberculosis, macrophages secrete a variety of chemoattractant cytokines, which help recruit uninfected macrophages, monocytes and lymphocytes from the circulation to the site of infection, initiating the formation of tuberculous granulomas [7]. Deciphering the functions of the various types of macrophages in tuberculous granulomas is important to elucidate the mechanism of tuberculous granuloma formation and development, and to improve our understanding of the general host immune response against M. tuberculosis
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