title: Effect of apoptotic cell recognition on macrophage polarization and mycobacterial persistence.
abstract: 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 investigated whether apoptotic cell removal (efferocytosis) induces different phenotypes in proinflammatory (Mϕ1) and anti-inflammatory (Mϕ2) 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 to resemble the Mϕ2 phenotype, displaying increased CD163 and SRA-I expression as well as higher phagocytic capacity. Efferocytosis increased M. leprae survival in Mϕ1 cells, accompanied by reduced interleukin-15 (IL-15) and IL-6 levels and increased transforming growth factor beta (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 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.
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: de Oliveira Fulco
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Priscila Ribeiro
authors.initials: PR
authors.lastname: Andrade
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Mayara Garcia
authors.initials: MG
authors.lastname: de Mattos Barbosa
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Thiago Gomes Toledo
authors.initials: TG
authors.lastname: Pinto
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Paula Fernandez
authors.initials: PF
authors.lastname: Ferreira
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Helen
authors.initials: H
authors.lastname: Ferreira
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: José Augusto
authors.initials: JA
authors.lastname: da Costa Nery
authors.affiliation: Structural Biology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Suzana Côrte
authors.initials: SC
authors.lastname: Real
authors.affiliation: Research Center of Gonçalo Moniz, Oswaldo Cruz Foundation, Salvador, BA, Brazil.
authors.forename: Valéria Matos
authors.initials: VM
authors.lastname: Borges
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Milton Ozório
authors.initials: MO
authors.lastname: Moraes
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Euzenir Nunes
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Elizabeth Pereira
authors.initials: EP
authors.lastname: Sampaio
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil robertaolmo@gmail.com.
authors.forename: Roberta Olmo
authors.initials: RO
authors.lastname: Pinheiro
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D007378:Interleukins / Q000276:immunology; D019169:Jurkat Cells; D007918:Leprosy / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology*; D009166:Mycobacterium leprae / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D007378:Interleukins; D016212:Transforming Growth Factor beta