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

Abstract

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.

Histoplasma capsulatum Cell Wall β-Glucan Induces Lipid Body Formation through CD18, TLR2, and Dectin-1 Receptors: Correlation with Leukotriene B4 Generation and Role in HIV-1 Infection

“…After staining, the slides were dried and mounted as described (18). Briefly, immediately after being harvested, total leukocytes from BALF of Hc-infected mice or PC of F1-, F2-, F3-, or ␤-glucaninoculated mice were used for LB enumeration and eicosanoid release.…”

“…An increase in LB numbers correlates with the concentrations of LTB 4 , LTC 4 , and PGE 2 released by leukocytes activated with the calcium ionophore A23187 (20,(22)(23)(24). Moreover, direct assessment of newly formed eicosanoids has characterized LBs as major sites of eicosanoid synthesis in inflammatory cells involved in allergic and infectious process (18,25,26).…”

Leptin and mTOR: Partners in metabolism and inflammation

“…40,82 Macrophage lipid bodies, which are formed by different stimuli and pathological conditions including obesity-induced inflammation, ox-LDL-and LPS-induced inflammation or bacterial infection, are increasingly recognized as organelles with key roles in inflammation. [83][84][85][86][87][88] Under inflammatory conditions, they compartmentalize MAP kinases, cPLA 2 , eicosanoid-forming enzymes and are involved in the enhanced eicosanoid synthesis. [84][85][86][87][88][89] In addition, human colon adenocarcinoma cell lines and colon cancer biopsies from patients have recently been shown to exhibit a drastic increase in ADRP and COX-2-enriched lipid bodies.…”

“…[83][84][85][86][87][88] Under inflammatory conditions, they compartmentalize MAP kinases, cPLA 2 , eicosanoid-forming enzymes and are involved in the enhanced eicosanoid synthesis. [84][85][86][87][88][89] In addition, human colon adenocarcinoma cell lines and colon cancer biopsies from patients have recently been shown to exhibit a drastic increase in ADRP and COX-2-enriched lipid bodies. 90 Furthermore, inhibition of lipid body formation leads to inhibited PGE 2 production and correlates with diminished cancer cell proliferation.…”

Avaliação da participação de mediadores lipídicos nas infecções experimentais induzidas por diferentes isolados de Mycobacterium tuberculosis de humanos

“…Salicilato de sódio e indometacina, também inibem a formação de CL em macrófagos [80,97] . Há evidências que confirmam a hipótese de que PGE 2 endógena derivada de CL modula a resposta inibitória em macrófagos infectados por micobactérias [37,99] . Assim, a inibição de CL em macrófagos não só leva à diminuição destas organelas, mas também aumenta a morte celular dos macrófagos infectados com micobactérias, dando suporte a hipótese de que os CLs podem ter implicações na patogênese da infecção por micobactéria [100] .…”