title: Enhancement of antimycobacterial activity of macrophages by stabilization of inner mitochondrial membrane potential.
abstract: Infection of human macrophages with Mycobacterium tuberculosis leads to cell death that, depending on the M. tuberculosis strain, time course, and multiplicity of infection, may have predominant features of apoptosis or necrosis. A key feature of infection-induced necrosis is mitochondrial damage characterized by an irreversible increase in the mitochondrial permeability transition (MPT), which is associated with increased release of cytochrome c from the mitochondria and uncontrolled mycobacterial replication. In contrast, protection of the mitochondria from MPT favors apoptosis of M. tuberculosis-infected macrophages. Apoptosis of M. tuberculosis-infected macrophages is associated with killing of intracellular M. tuberculosis, and this may be enhanced when MPT is stabilized. Here, we show that cyclosporin A (CsA), an inhibitor of MPT, protects the mitochondria from release of cytochrome c and promotes the antimycobacterial activity of macrophages infected with M. tuberculosis H37Ra. Signaling by purinergic P2 receptors has previously been linked to the antimycobacterial activity of macrophages. In the present study, we found that infection with H37Ra inhibits P2X7 receptor (P2XR) signals and that CsA restores P2XR function in infected macrophages. Together, these data demonstrate that CsA promotes at least 2 antimycobacterial pathways of macrophages.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Huixian
authors.initials: H
authors.lastname: Gan
authors.forename: Xianbao
authors.initials: X
authors.lastname: He
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mirabile-Levens
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002470:Cell Survival; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D016676:Macrophages, Alveolar / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D009336:Necrosis; D018048:Receptors, Purinergic P2 / Q000378:metabolism
chemical_list: D018048:Receptors, Purinergic P2; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D045304:Cytochromes c