PT  - JOURNAL ARTICLE
AU  - Rajaram, Murugesan V. S.
AU  - Brooks, Michelle N.
AU  - Morris, Jessica D.
AU  - Torrelles, Jordi B.
AU  - Azad, Abul K.
AU  - Schlesinger, Larry S.
TI  - <em>Mycobacterium tuberculosis</em> Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ Linking Mannose Receptor Recognition to Regulation of Immune Responses
AID  - 10.4049/jimmunol.1000866
DP  - 2010 Jul 15
TA  - The Journal of Immunology
PG  - 929--942
VI  - 185
IP  - 2
4099  - http://www.jimmunol.org/content/185/2/929.short
4100  - http://www.jimmunol.org/content/185/2/929.full
SO  - J. Immunol.2010 Jul 15; 185
AB  - Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARγ expression through a macrophage mannose receptor-dependent pathway. When activated, PPARγ promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARγ agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A2 activation, which is required for PPARγ ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-κB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARγ and preferentially uses the NF-κB–mediated pathway to induce IL-8 production. Finally, PPARγ 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 PPARγ activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.