title: Electrophysiological characterization of the first Tityus serrulatus alpha-like toxin, Ts5: Evidence of a pro-inflammatory toxin on macrophages.
abstract: Tityus serrulatus (Ts) venom is composed of mainly neurotoxins specific for voltage-gated K(+) and Na(+) channels, which are expressed in many cells such as macrophages. Macrophages are the first line of defense invasion and they participate in the inflammatory response of Ts envenoming. However, little is known about the effect of Ts toxins on macrophage activation. This study investigated the effect of Ts5 toxin on different sodium channels as well as its role on the macrophage immunomodulation. The electrophysiological assays showed that Ts5 inhibits the rapid inactivation of the mammalian sodium channels Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6 and Nav1.7. Interestingly, Ts5 also inhibits the inactivation of the insect Drosophila melanogaster sodium channel (DmNav1), and it is therefore classified as the first Ts α-like toxin. The immunological experiments on macrophages reveal that Ts5 is a pro-inflammatory toxin inducing the cytokine production of tumor necrosis factor (TNF)-α and interleukin (IL)-6. On the basis of recent literature, our study also stresses a possible mechanism responsible for venom-associated molecular patterns (VAMPs) internalization and macrophage activation and moreover we suggest two main pathways of VAMPs signaling: direct and indirect. This work provides useful insights for a better understanding of the involvement of VAMPs in macrophage modulation.
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Manuela B
authors.initials: MB
authors.lastname: Pucca
authors.affiliation: Toxicology and Pharmacology, University of Leuven, Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Camila T
authors.initials: CT
authors.lastname: Cologna
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Cerni
authors.affiliation: Department of Clinical Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Karina F
authors.initials: KF
authors.lastname: Zoccal
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Karla de C F
authors.initials: Kde C
authors.lastname: Bordon
authors.affiliation: Department of Clinical Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Lucia H
authors.initials: LH
authors.lastname: Faccioli
authors.affiliation: Toxicology and Pharmacology, University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: ecabraga@fcfrp.usp.br.
authors.forename: Eliane C
authors.initials: EC
authors.lastname: Arantes
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004331:Drosophila melanogaster; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D009569:Nitric Oxide / Q000378:metabolism; D012604:Scorpion Venoms / Q000633:toxicity*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D016207:Cytokines; D009498:Neurotoxins; D012604:Scorpion Venoms; C581454:Ts6 toxin, Tityus serrulatus; D061566:Voltage-Gated Sodium Channels; D009569:Nitric Oxide
keywords: Macrophage modulation; Sodium channel; Tityus serrulatus; Toxin; Ts5