Toll-Like Receptor-2-Mediated C-C Chemokine Receptor 3 and Eotaxin-Driven Eosinophil Influx Induced by
            <i>Mycobacterium bovis</i>
            BCG Pleurisy

D’Avila, Heloísa; Almeida, Patrícia E. de; Roque, Natália R.; Castro‐Faria‐Neto, Hugo C.; Bozza, Patrı́cia T.

doi:10.1128/iai.01326-06

Cited by 32 publications

(33 citation statements)

References 28 publications

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“…The role of TLR-mediated pathogen recognition and activation in the mechanism of lipid body formation has been documented (4,5,28,32). The role of TLR2 in regulating PPAR␥ expression during BCG infection in vitro was investigated.…”

Section: Induction Of Ppar␥ Expression By Bcg Infection Depends On Tlmentioning

confidence: 99%

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

Almeida¹,

Silva

Maya‐Monteiro³

et al. 2009

The Journal of Immunology

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164

194

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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.

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Section: Induction Of Ppar␥ Expression By Bcg Infection Depends On Tlmentioning

confidence: 99%

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

Almeida¹,

Silva

Maya‐Monteiro³

et al. 2009

The Journal of Immunology

Self Cite

164

194

View full text Add to dashboard Cite

show abstract

“…Specifically in macrophages, it has been shown that the genesis of new lipid bodies can be evoked by a variety of inflammation-related stimuli, including oxidized low-density lipoprotein (oxLDL) and oxLDL-components (but not native LDL) acting through membrane and nuclear receptors (9 -12). Pathogens including Grampositive (Mycobacterium bovis bacillus Calmette-Guérin) and Gram-negative bacteria (Escherichia coli) (13)(14)(15)(16), Chlamydia pneumoniae (17) and Trypanosoma cruzi (18), as well as pathogen-related molecules (LPS and lipoarabinomannan) (13,14) acting through their specific receptors (CD14, TLR4, and TLR2) (13,14) were also shown to elicit signaling that culminate with activation of ER-assembling lipid body machinery. Downstream to the activation by pathogen-derived molecules, endogenous molecules-yet to be characterized-may also trigger lipid body biogenesis during infection-driven inflammation therefore comprising potential therapeutical targets for lipid body regulated pathologies.…”

mentioning

confidence: 99%

Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 Controls Microtubule-Driven Biogenesis and Leukotriene B4-Synthesizing Function of Macrophage Lipid Bodies Elicited by Innate Immune Response

Pacheco

Vieira‐de‐Abreu

Gomes

et al. 2007

The Journal of Immunology

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112

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Lipid bodies (also known as lipid droplets) are emerging as inflammatory organelles with roles in the innate immune response to infections and inflammatory processes. In this study, we identified MCP-1 as a key endogenous mediator of lipid body biogenesis in infection-driven inflammatory disorders and we described the cellular mechanisms and signaling pathways involved in the ability of MCP-1 to regulate the biogenesis and leukotriene B4 (LTB4) synthetic function of lipid bodies. In vivo assays in MCP-1−/− mice revealed that endogenous MCP-1 produced during polymicrobial infection or LPS-driven inflammatory responses has a critical role on the activation of lipid body-assembling machinery, as well as on empowering enzymatically these newly formed lipid bodies with LTB4 synthetic function within macrophages. MCP-1 triggered directly the rapid biogenesis of distinctive LTB4-synthesizing lipid bodies via CCR2-driven ERK- and PI3K-dependent intracellular signaling in in vitro-stimulated macrophages. Disturbance of microtubule organization by microtubule-active drugs demonstrated that MCP-1-induced lipid body biogenesis also signals through a pathway dependent on microtubular dynamics. Besides biogenic process, microtubules control LTB4-synthesizing function of MCP-1-elicited lipid bodies, in part by regulating the compartmentalization of key proteins, as adipose differentiation-related protein and 5-lipoxygenase. Therefore, infection-elicited MCP-1, besides its known CCR2-driven chemotactic function, appears as a key activator of lipid body biogenic and functional machineries, signaling through a microtubule-dependent manner.

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“…7 In other models of pathogen-induced eosinophilia, it has been shown that direct stimulation of TLR2 by M. bovis can induce an eosinophilic infiltration into the pleural cavity that is highly dependent on IL-5, CCL11, and the CCL11 receptor CCR3. 28 Our results suggest that TLR2-mediated eosinophil recruitment also occurs in the gastrointestinal tract, potentially as a result of exposure of effector cells to products of the bacterial flora.…”

Section: Discussionmentioning

confidence: 66%

“…27 Stimulation of TLR2 by Mycobacterium bovis has also been shown to induce an eosinophilic infiltration into the pleural cavity that is highly dependent on IL-5, CCL11, and CCR3 (a CCL11 receptor). 28 The role of TLR2 in eosinophil recruitment during DSS colitis and the potential role of eosinophils in the severe colitis seen in TLR2 Ϫ/Ϫ mice have not been previously examined.…”

mentioning

confidence: 99%

Tissue Eosinophilia in a Mouse Model of Colitis Is Highly Dependent on TLR2 and Independent of Mast Cells

Albert

Duplisea

Dawicki

et al. 2011

The American Journal of Pathology

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The mechanisms initiating eosinophil influx into sites of inflammation have been well studied in allergic disease but are poorly understood in other settings. This study examined the roles of TLR2 and mast cells in eosinophil accumulation during a nonallergic model of eosinophilia-associated colitis. TLR2-deficient mice (TLR2 ؊/؊ ) developed a more severe colitis than wild-type mice in the dextran sodium sulfate (DSS) model. However, they had significantly fewer eosinophils in the submucosa of the cecum (P < 0.01) and mid-colon (P < 0.01) than did wild-type mice after DSS treatment. Decreased eosinophilia in TLR2 ؊/؊ mice was associated with lower levels of cecal CCL11 (P < 0.01). Peritoneal eosinophils did not express TLR2 protein, but TLR2 ligand injection into the peritoneal cavity induced local eosinophil recruitment, indicating that TLR2 activation of other cell types can mediate eosinophil recruitment. After DSS treatment, mast celldeficient (Kit W-sh/W-sh ) mice had similar levels of intestinal tissue eosinophilia were observed as those in wild-type mice. However, mast cell-deficient mice were partially protected from DSS-induced weight loss, an effect that was reversed by mast cell reconstitution. Overall, this study indicates a critical role for indirect TLR2-dependent pathways, but not mast cells, in the generation of eosinophilia in the large intestine during experimental colitis and has important implications for the regulation of eosinophils at mucosal inflammatory sites.

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Toll-Like Receptor-2-Mediated C-C Chemokine Receptor 3 and Eotaxin-Driven Eosinophil Influx Induced by Mycobacterium bovis BCG Pleurisy

Cited by 32 publications

References 28 publications

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

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

Monocyte Chemoattractant Protein-1/CC Chemokine Ligand 2 Controls Microtubule-Driven Biogenesis and Leukotriene B4-Synthesizing Function of Macrophage Lipid Bodies Elicited by Innate Immune Response

Tissue Eosinophilia in a Mouse Model of Colitis Is Highly Dependent on TLR2 and Independent of Mast Cells

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