The Effect of Apoptotic Cell Recognition on Macrophage Polarization and Mycobacterial Persistence.
Intracellular Mycobacterium leprae infection modifies host macrophage programming, creating a protective niche for bacterial survival. The milieu regulating cellular apoptosis in the tissue plays an important role in defining susceptible and/or resistant phenotypes. A higher density of apoptotic cells has been demonstrated in paucibacillary leprosy lesions than in multibacillary ones. However, the effect of apoptotic cell removal on M. leprae-stimulated cells has yet to be fully elucidated. In this study, we investigate whether apoptotic cell removal (efferocytosis) induces different phenotypes in pro- (Mφ1) and anti- (Mφ2) inflammatory macrophages in the presence of M. leprae. We stimulated Mφ1 and Mφ2 cells with M. leprae in the presence or absence of apoptotic cells and subsequently evaluated the M. leprae uptake, cell phenotype, and cytokine pattern in the supernatants. In the presence of M. leprae and apoptotic cells, Mφ1 macrophages changed their phenotype towards Mφ2, displaying increased CD163 and SRA-I expression as well as higher phagocytic capacity. Efferocytosis increased M. leprae survival in Mφ1 cells, accompanied by reduced IL-15 and IL-6 and increased TGF-β and IL-10 secretion. Mφ1 cells primed with M. leprae in the presence of apoptotic cells induced the secretion of Th2 cytokines IL-4 and IL-13 in autologous T cells when compared with cultures stimulated with M. leprae or apoptotic cells alone. Efferocytosis did not alter the Mφ2 cell phenotype or cytokine secretion profile, except for TGF-β. Based on these data, we suggest that, in paucibacillary leprosy patients, efferocytosis contributes to mycobacterial persistence by increasing the Mφ2 population and sustaining the infection.