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

Abstract

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 γ (PPARγ). We found that BCG infection induced increased expression of PPARγ that paralleled the augmented lipid body formation and PGE2 synthesis in mouse peritoneal macrophages. BCG-induced PPARγ expression and lipid body formation were diminished in macrophages from TLR2-deficient mice, suggesting a key role for TLR2. The function of PPARγ in modulating BCG infection was demonstrated by the capacity of the PPARγ agonist BRL49653 to potentiate lipid body formation and PGE2 production; furthermore, pretreatment with the PPARγ antagonist GW9662 inhibited BCG-induced lipid body formation and PGE2 production. BCG-induced MIP-1α, IL12p70, TNF-α, and IL6 production was not inhibited by GW9662 treatment. Nonpathogenic Mycobacterium smegmatis failed to induce PPARγ expression or lipid body formation. Moreover, inhibition of PPARγ by GW9662 enhanced the mycobacterial killing capacity of macrophages. Our findings show that PPARγ is involved in lipid body biogenesis, unravels a cross-talk between the innate immune receptor TLR2 and the lipid-activated nuclear receptor PPARγ that coordinates lipid metabolism and inflammation in BCG-infected macrophages, thereby potentially affecting mycobacterial pathogenesis.

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

“…PPAR␥ and TR4 provoke anti-inflammatory and pro-mycobacterium properties of macrophages (16,17,25), whereas vitamin D receptor and LXRs on the other hand have anti-inflammatory but anti-infective or bactericidal properties (39,40). Similarly, we observe that Rev-erb␣ facilitates M. tuberculosis clearance as an effect of its role in reducing IL10 production (Fig.…”

Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2-dependent peroxisome proliferator-activated receptor γ expression and promotes inflammatory responses in human macrophages

“…1D) were also analyzed. Two-way ANOVA revealed significant effects of time (F time(4,30) =16.29, P<0.0001) and infection/treatment (F infection(2,30) =57.64, P<0.0001) on IL-6 production, as well as an interaction between them (F interaction (8,30) =4.46, P<0.01). Similarly, the levels of TNF-α were also significantly affected by time (F time(4,30) =25.92, P<0.0001) and infection/treatment (F infection(2,30) =3.94, P<0.05); however, no significant effect of time-infection interaction was detected (F interaction (8,30) =2.95, P=0.07).…”

“…3A). Two-way ANOVA revealed a significant effect of TLR2 knockdown (F TLR2-siRNA (1,8) =70.4, P<0.0001) and P19 treatment (F P19 (1,8) =23.3, P<0.01) on PPARγ mRNA expression, as well as an interaction between them (F interaction (1,8) =21.8, P<0.01) (Fig. 3B).…”

“…PPARγ, a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and is highly expressed in alternatively activated alveolar macrophages and macrophage-derived foam cells, both of which are closely associated with the pathogenesis of tuberculosis (7). A previous study demonstrated that PPARγ is involved in lipid body biogenesis, revealing a cross-talk between the innate immune receptor Toll-like receptor 2 (TLR2) and the lipid-activated nuclear receptor PPARγ that coordinates lipid metabolism and inflammation in the Bacillus Calmette-Guérin (BCG)-infected macrophages, thereby potentially altering mycobacterial pathogenesis (8). Although it is well established that PPARγ acts as a master regulator in lipid metabolism and inflammation, the involvement of PPARγ in the immune response of macrophages to intracellular pathogen infection remains to be elucidated.…”

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

“…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] . [102] .…”