<i>Histoplasma capsulatum</i> 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

Sorgi, Carlos Artério; Secatto, Adriana; Fontanari, Caroline; Turato, Walter Miguel; Bélanger, Caroline; Medeiros, Alexandra I.; Kashima, Simone; Marleau, Sylvie; Covas, Dimas Tadeu; Bozza, Patrı́cia T.; Faccioli, Lúcia Helena

doi:10.4049/jimmunol.0801795

Cited by 63 publications

(60 citation statements)

References 53 publications

(53 reference statements)

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“…This finding suggests that TLR2 activation, although essential for mycobacteriainduced lipid body formation, is not sufficient to trigger pathways of lipid body formation and other cofactors may be involved. Indeed, cofactors for TLR activation to form lipid bodies have been described in LPS stimulation and Histoplasma capsulatum infection (27,50). Accordingly, TLR2-dependent signaling may be modulated by the concomitant interaction with coreceptors and, depending on the coreceptor used, distinct downstream signaling pathways may be recruited, leading to differential cellular compartmentalization and responses (51)(52)(53)(54).…”

Section: Discussionmentioning

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

151

191

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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: Discussionmentioning

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

151

191

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“…Engagement of TLRs leads to activation of signaling pathways that results in generation of cytokines, chemokines, and lipid mediators produced by cyclooxygenases that are critical for host immune response (19,20). We and others have shown that activation of cyclooxygenase-2 (COX-2) and production of lipid mediators play a pivotal immunomodulatory role in fungal, viral, and bacterial infections (21)(22)(23)(24)(25). In particular, PGE 2 has immunosuppressive effects and impairs bacterial clearance (22,23,(26)(27)(28)(29), whereas PGD 2 has been shown to have immunostimulatory effects (30,31).…”

mentioning

confidence: 99%

Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

Yuan

Panchal

Syed

et al. 2013

The Journal of Immunology

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Stomatococcus mucilaginosus is an oral commensal that has been occasionally reported to cause severe infections in immunocompromised patients. There is no information about the pathogenic role of S. mucilaginosus in airway infections. In a cohort of 182 subjects with bronchiectasis, we found that 9% were colonized with S. mucilaginosus in their lower airways by culture growth from bronchoalveolar lavage. To address the pathogenic potential of S.mucilaginosus, we developed a murine model of S. mucilaginosus lung infection. Intratracheal injection of S. mucilaginosus in C57BL/6 mice resulted in a neutrophilic influx with production of proinflammatory cytokines, chemokines, and lipid mediators, mainly PGE2 with induction of cyclooxygenase-2 (COX-2) in the lungs. Presence of TLR2 was necessary for induction of COX-2 and production of PGE2 by S. mucilaginosus. TLR2-deficient mice showed an enhanced clearance of S. mucilaginosus compared with wild-type mice. Administration of PGE2 to TLR2−/− mice resulted in impaired clearance of S. mucilaginosus, suggesting a key role for COX-2–induced PGE2 production in immune response to S. mucilaginosus. Mechanistically, induction of COX-2 in macrophages was dependent on the p38-ERK/MAPK signaling pathway. Furthermore, mice treated with S. mucilaginosus and Pseudomonas aeruginosa showed an increased mortality compared with mice treated with PA103 or S. mucilaginosus alone. Inhibition of COX-2 significantly improved survival in mice infected with PA103 and S. mucilaginosus. These data provide novel insights into the bacteriology and personalized microbiome in patients with bronchiectasis and suggest a pathogenic role for S. mucilaginosus in patients with bronchiectasis.

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“…The formation of lipid bodies (multifunctional organelles with critical roles in inflammation) induced by Histoplasma capsulatum ␤-glucan was inhibited in TLR2-deficient mice (47). Chitin, a cell wall structural polysaccharide, has been consistently characterized as a stimulator of TLR2-dependent production of interleukin 17 (IL-17) by macrophages, resulting in the induction of acute inflammation (7).…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effects of Serotype B Glucuronoxylomannan from Cryptococcus gattii Correlate with Polysaccharide Diameter

Fonseca

Nohara

Cordero³

et al. 2010

Infect Immun

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Glucuronoxylomannan (GXM), the major capsular component in the Cryptococcus complex, interacts with the immune system in multiple ways, which include the activation of Toll-like receptors (TLRs) and the modulation of nitric oxide (NO) production by phagocytes. In this study, we analyzed several structural parameters of GXM samples from Cryptococcus neoformans (serotypes A and D) and Cryptococcus gattii (serotypes B and C) and correlated them with the production of NO by phagocytes and the activation of TLRs. GXM fractions were differentially recognized by TLR2/TLR1 (TLR2/1) and TLR2/6 heterodimers expressed on TLR-transfected HEK293A cells. Higher NF-B luciferase reporter activity induced by GXM was observed in cells expressing TLR2/1 than in cells transfected with TLR2/6 constructs. A serotype B GXM from C. gattii was the most effective polysaccharide fraction activating the TLR-mediated response. This serotype B polysaccharide, which was also highly efficient at eliciting the production of NO by macrophages, was similar to the other GXM samples in monosaccharide composition, zeta potential, and electrophoretic mobility. However, immunofluorescence with four different monoclonal antibodies and dynamic light-scattering analysis revealed that the serotype B GXM showed particularities in serological reactivity and had the smallest effective diameter among the GXM samples analyzed in this study. Fractionation of additional serotype B GXMs, followed by exposure of these fractions to macrophages, revealed a correlation between NO production and reduced effective diameters. Our results demonstrate a great functional diversity in GXM samples from different isolates and establish their abilities to differentially activate cellular responses. We propose that serological properties as well as physical chemical parameters, such as the diameter of polysaccharide molecules, may potentially influence the inflammatory response against Cryptococcus spp. and may contribute to the differences in granulomatous inflammation between cryptococcal species.

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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

Cited by 63 publications

References 53 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

Induction of Cyclooxygenase-2 Signaling by Stomatococcus mucilaginosus Highlights the Pathogenic Potential of an Oral Commensal

Immunomodulatory Effects of Serotype B Glucuronoxylomannan from Cryptococcus gattii Correlate with Polysaccharide Diameter

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