Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ 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.