title: Differential TLR2 downstream signaling regulates lipid metabolism and cytokine production triggered by Mycobacterium bovis BCG infection.
abstract: The nuclear receptor PPARγ acts as a key modulator of lipid metabolism, inflammation and pathogenesis in BCG-infected macrophages. However, the molecular mechanisms involved in PPARγ expression and functions during infection are not completely understood. Here, we investigate signaling pathways triggered by TLR2, the involvement of co-receptors and lipid rafts in the mechanism of PPARγ expression, lipid body formation and cytokine synthesis in macrophages during BCG infection. BCG induces NF-κB activation and increased PPARγ expression in a TLR2-dependent manner. Furthermore, BCG-triggered increase of lipid body biogenesis was inhibited by the PPARγ antagonist GW9662, but not by the NF-κB inhibitor JSH-23. In contrast, KC/CXCL1 production was largely dependent on NF-κB but not on PPARγ. BCG infection induced increased expression of CD36 in macrophages in vitro. Moreover, CD36 co-immunoprecipitates with TLR2 in BCG-infected macrophages, suggesting its interaction with TLR2 in BCG signaling. Pretreatment with CD36 neutralizing antibodies significantly inhibited PPARγ expression, lipid body formation and PGE2 production induced by BCG. Involvement of CD36 in lipid body formation was further confirmed by decreased BCG-induced lipid body formation in CD36 deficient macrophages. Similarly, CD14 and CD11b/CD18 blockage also inhibited BCG-induced lipid body formation, whereas TNF-α synthesis was not affected. Disruption of rafts recapitulates the latter result, inhibiting lipid body formation, but not TNF-α synthesis in BCG-infected macrophages. In conclusion, our results suggest that CD36-TLR2 cooperation and signaling compartmentalization within rafts, divert host response signaling through PPARγ-dependent and NF-κB-independent pathways, leading to increased macrophage lipid accumulation and down-modulation of macrophage response.
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Laboratório de Biologia Celular, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil.
authors.forename: Patrícia E
authors.initials: PE
authors.lastname: Almeida
authors.forename: Natália R
authors.initials: NR
authors.lastname: Roque
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Magalhães
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Mattos
authors.forename: Livia
authors.initials: L
authors.lastname: Teixeira
authors.forename: Clarissa
authors.initials: C
authors.lastname: Maya-Monteiro
authors.forename: Cecília J
authors.initials: CJ
authors.lastname: Almeida
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valérie F J
authors.initials: VF
authors.lastname: Quesniaux
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics; D054360:Chemokine CXCL1 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D050356:Lipid Metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D010655:Phenylenediamines / Q000494:pharmacology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C457499:2-chloro-5-nitrobenzanilide; C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; D000813:Anilides; D039481:CD11b Antigen; D018821:CD18 Antigens; D018955:CD36 Antigens; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D047495:PPAR gamma; D010655:Phenylenediamines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha
keywords: ADRP; BCG; Bacillus Calmette Guérin; CD36; IL; Lipid droplet; Mβ-CD; NF-κB; Nuclear receptor; PAMP; PGE(2); PPARgamma; PPARγ; TLR; Toll-like receptor; adipose differentiation related protein; interleukin; methyl-β-cyclodextrin; nuclear factor-κB; pathogen-associated molecular patterns; peroxisome proliferator-activated receptor gamma; prostaglandin E(2)