Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ Linking Mannose Receptor Recognition to Regulation of Immune Responses

Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor gamma (PPAR gamma), 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 PPAR gamma expression through a macrophage mannose receptor-dependent pathway. When activated, PPAR gamma promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPAR gamma agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A(2) activation, which is required for PPAR gamma ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-kappa B activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guerin induces less PPAR gamma and preferentially uses the NF-kappa B-mediated pathway to induce IL-8 production. Finally, PPAR gamma 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 PPAR gamma activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis. The Journal of Immunology, 2010, 185: 929-942.