PPAR-γ activation by Tityus serrulatus venom regulates lipid body formation and lipid mediator production

• Published in: Toxicon (Oxford) 2015-01, Vol.93, p.90-97
• Main Authors: Zoccal, Karina Furlani, Paula-Silva, Francisco Wanderley Garcia, Bitencourt, Claudia da Silva, Sorgi, Carlos Artério, Bordon, Karla de Castro Figueiredo, Arantes, Eliane Candiani, Faccioli, Lúcia Helena
• Format: Article
• Language: English
• Subjects: Activation; Analysis of Variance; Animals; Cytokines; Cytokines - immunology; Dinoprostone - immunology; Formations; Humans; Leukotriene B4 - immunology; Leukotrienes; Lipid bodies; Lipid Droplets - physiology; Lipids; Macrophages; Mice; Mice, Knockout; NF-kappa B; Patients; Peptides; Peroxisome proliferator-activated receptor gamma; PPAR gamma - metabolism; Prostaglandins; Real-Time Polymerase Chain Reaction; Receptors; Recognition; Scorpion Stings - immunology; Scorpion Stings - metabolism; Scorpion Venoms - toxicity; Scorpions; Signal Transduction - immunology; Tityus serrulatus; Tityus serrulatus venom; Toll-like receptors
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2014.11.226

Tityus serrulatus venom (TsV) consists of numerous peptides with different physiological and pharmacological activities. Studies have shown that scorpion venom increases pro-inflammatory cytokine production, contributing to immunological imbalance, multiple organ dysfunction, and patient death. We have previously demonstrated that TsV is a venom-associated molecular pattern (VAMP) recognized by TLRs inducing intense inflammatory reaction through the production of pro-inflammatory cytokines and arachidonic acid-derived lipid mediators prostaglandin (PG)E2 and leukotriene (LT)B4. Lipid bodies (LBs) are potential sites for eicosanoid production by inflammatory cells. Moreover, recent studies have shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) is implicated in LB formation and acts as an important modulator of lipid metabolism during inflammation. In this study, we used murine macrophages to evaluate whether the LB formation induced by TsV after TLR recognition correlates with lipid mediator generation by macrophages and if it occurs through PPAR-γ activation. We demonstrate that TsV acts through TLR2 and TLR4 stimulation and PPAR-γ activation to induce LB formation and generation of PGE2 and LTB4. Our data also show that PPAR-γ negatively regulates the pro-inflammatory NF-κB transcription factor. Based on these results, we suggest that during envenomation, LBs constitute functional organelles for lipid mediator production through signaling pathways that depend on cell surface and nuclear receptors. These findings point to the inflammatory mechanisms that might also be triggered during human envenomation by TsV. •TsV-induced LB formation is dependent on TLR4/TLR2 recognition and PPAR-γ activation.•TsV-induced PPAR-γ activation results in LB formation, and PGE2 and LTB4 production.•TsV-induced LB formation correlates with lipid mediator release.