HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: jimmunol.0900365v1 183/2/1337    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Almeida, P. E. Articles by Bozza, P. T. PubMed PubMed Citation Articles by Almeida, P. E. Articles by Bozza, P. T.

Mycobacterium bovis Bacillus Calmette-Guérin Infection Induces TLR2-Dependent Peroxisome Proliferator-Activated Receptor Expression and Activation: Functions in Inflammation, Lipid Metabolism, and Pathogenesis¹

Patrícia E. Almeida^*, Adriana R. Silva, Clarissa M. Maya-Monteiro^*, Dániel Töröcsik, Heloisa D Ávila^*, Balázs Dezsö, Kelly G. Magalhães^*, Hugo C. Castro-Faria-Neto^*, Laszlo Nagy and Patrícia T. Bozza^*,2

*Laboratório de Imunofarmacologia Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; and Department of Biochemistry and Molecular Biology and Department of Pathology, Medical and Health Science Center, Research Center for Molecular Medicine, University of Debrecen, Hungary

Macrophages have important roles in both lipid metabolism and inflammation and are central to immunity to intracellular pathogens. Foam-like, lipid-laden macrophages are present during the course of mycobacterial infection and have recently been implicated in mycobacterial pathogenesis. In this study, we analyzed the molecular mechanisms underlying the formation of macrophage lipid bodies (lipid droplets) during Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection, focusing on the role of the lipid-activated nuclear receptor peroxisome proliferator-activated receptor (PPAR). We found that BCG infection induced increased expression of PPAR that paralleled the augmented lipid body formation and PGE₂ synthesis in mouse peritoneal macrophages. BCG-induced PPAR expression and lipid body formation were diminished in macrophages from TLR2-deficient mice, suggesting a key role for TLR2. The function of PPAR in modulating BCG infection was demonstrated by the capacity of the PPAR agonist BRL49653 to potentiate lipid body formation and PGE₂ production; furthermore, pretreatment with the PPAR antagonist GW9662 inhibited BCG-induced lipid body formation and PGE₂ production. BCG-induced MIP-1, IL12p70, TNF-, and IL6 production was not inhibited by GW9662 treatment. Nonpathogenic Mycobacterium smegmatis failed to induce PPAR expression or lipid body formation. Moreover, inhibition of PPAR by GW9662 enhanced the mycobacterial killing capacity of macrophages. Our findings show that PPAR is involved in lipid body biogenesis, unravels a cross-talk between the innate immune receptor TLR2 and the lipid-activated nuclear receptor PPAR that coordinates lipid metabolism and inflammation in BCG-infected macrophages, thereby potentially affecting mycobacterial pathogenesis.

²Address correspondence and reprint requests to Dr. Patrícia T. Bozza, Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz; Avenida Brasil 4365, Manguinhos; 21045-900 Rio de Janeiro, RJ, Brazil. E-mail address: pbozza{at}ioc.fiocruz.br

¹ This work was supported by a mini-grant from the Howard Hughes Medical Institute to P.T.B. and L.N. and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (Brazil), Programa Núcleos de Excelência (Brazil), and Programa de Apoio a Pesquisa Estrategica em Saude (Fundaçcao Oswaldo Cruz, Brazil). L.N. is an International Scholar of the Howard Hughes Medical Institute and holds a Wellcome Trust Senior Research Fellowship in Biomedical Sciences in Central Europe.