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The Journal of Immunology, 2006, 176: 3087-3097.
Copyright © 2006 by The American Association of Immunologists

Mycobacterium bovis Bacillus Calmette-Guérin Induces TLR2-Mediated Formation of Lipid Bodies: Intracellular Domains for Eicosanoid Synthesis In Vivo1

Heloisa D’Avila*, Rossana C. N. Melo{dagger}, Gleydes G. Parreira{ddagger}, Eduardo Werneck-Barroso§, Hugo C. Castro-Faria-Neto* and Patrícia T. Bozza2,*

* Laboratório de Imunofarmacologia, Departamento de Fisiologia e Farmacodinamica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; {dagger} Laboratório de Biologia Celular, Departamento de Biologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil; {ddagger} Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; and § Laboratório de Farmacocinética, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil

Differentiation of macrophages into foamy (lipid-laden) macrophages is a common pathological observation in tuberculous granulomas both in experimental settings as well as in clinical conditions; however, the mechanisms that regulate intracellular lipid accumulation in the course of mycobacterial infection and their significance to pathophysiology of tuberculosis are not well understood. In this study, we investigated the mechanisms of formation and function of lipid-laden macrophages in a murine model of tuberculosis. Mycobacterium bovis bacillus Calmette-Guérin (BCG), but not Mycobacterium smegmatis, induced a dose- and time-dependent increase in lipid body-inducible nonmembrane-bound cytoplasmic lipid domain size and numbers. Lipid body formation was drastically inhibited in TLR2-, but not in TLR4-deficient mice, indicating a role for TLR2 in BCG recognition and signaling to form lipid bodies. Increase in lipid bodies during infection correlated with increased generation of PGE2 and localization of cyclooxygenase-2 within lipid bodies. Moreover, we demonstrated by intracellular immunofluorescent localization of newly formed eicosanoid that lipid bodies were the predominant sites of PGE2 synthesis in activated macrophages. Our findings demonstrated that BCG-induced lipid body formation is TLR2 mediated and these structures function as signaling platforms in inflammatory mediator production, because compartmentalization of substrate and key enzymes within lipid bodies has impact on the capacity of activated leukocytes to generate increased amounts of eicosanoids during experimental infection by BCG.




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