title: Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses.
abstract: Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPARgamma expression through a macrophage mannose receptor-dependent pathway. When activated, PPARgamma promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARgamma agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A(2) activation, which is required for PPARgamma ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-kappaB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARgamma and preferentially uses the NF-kappaB-mediated pathway to induce IL-8 production. Finally, PPARgamma knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPARgamma activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.
authors.affiliation: Center for Microbial Interface Biology, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Brooks
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Morris
authors.forename: Jordi B
authors.initials: JB
authors.lastname: Torrelles
authors.forename: Abul K
authors.initials: AK
authors.lastname: Azad
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D000813:Anilides / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism*; D018448:Models, Immunological; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016209:Interleukin-8; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D016328:NF-kappa B; D047495:PPAR gamma; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C050016:lipoarabinomannan; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D054510:Phospholipases A2, Cytosolic