Immunomodulation of the Inflammatory Response Induced by Androctonus australis hector Neurotoxins: Biomarker Interactions

Abstract

Objective:Androctonus australis hector (Aah) is the most dangerous scorpion in the Maghreb countries. Its venom contains three major neurotoxins (Aah I, Aah II and Aah III), which are responsible for almost all the lethal effects caused in mammals. These toxins act on the voltage-gated sodium channels of excitable cells. The targets and the lethal effects of these toxins have been extensively studied. However, their effects on the induced immune response after envenoming have not deeply elicited. We therefore investigated the effects induced by Aah venom and its toxic components, mainly its main toxin Aah II, on the activation of the inflammatory process. Methods: Wistar rats were injected by intraperitoneal route with a sublethal dose of Aah venom, FTox-G50, the purified Aah II toxin or with 400 µl of sterile physiological saline solution. Immunological biomarkers such as MPO, NO and ICAM-1 were analyzed in serum in lung tissue. Cytokine levels were also determined in serum at 3, 6 and 24 h after envenoming. Results: We report in this study that intraperitoneal injection of the venom or its toxins (the whole toxic fraction or Aah II toxin) caused an inflammatory reaction involving increased neutrophil release into blood and neutrophil accumulation in lung tissue. This cell infiltration was associated with the release of NO, histamine, cytokines (IL-1, IL-6, IL-12, IL-4 and IL-5) and ICAM. Conclusion: Aah II binding to its targets, in this case Na⁺ channels, may induce a cascade of events such as inflammatory mediator release and neutrophil migration that could contribute to the exacerbation of the systemic inflammatory response and the development of lung injury following scorpion envenoming.

Scorpion Venom Interactions with the Immune System

“…NO plays a role in immunity and inflammation but also in neurotransmission, muscle relaxation, and vasodilatation. An increase of NO levels in the serum or in peritoneal macrophage culture correlated with production of pro-inflammatory cytokines has been shown after experimental and accidental SE (Meki and Mohey El-Dean 1998;Petricevich and Peña 2002;Pessini et al 2006;Zoccal et al 2011;Raouraoua-Boukari et al 2012). These high concentration of NO may be associated with severe conditions, such as septic shock, hypertension, febrile response, and severe SE (Petricevich and Peña 2002;Pessini et al 2006;Petricevich 2010).…”

“…These mediators may be derived from macrophages and epithelial cells, but the neutrophil itself is a major source of IL-8. Thus, adherent neutrophils produce and release oxygen free radicals and enzymes, such as proteases (e.g., elastase and metalloproteinases) and myeloperoxidase (MPO), exacerbating damage to endothelial cells and inducing tissue injury after SE (Coelho et al 2007;Adi-Bessalem et al 2012;Raouraoua-Boukari et al 2012). Polymorphonuclear activation and migration is a result of a cascade of cellular events, in which polymorphonuclear and endothelial cells and macrophages act in concert (Fig.…”

“…Oxidative stress originates mainly in mitochondria from reactive oxygen and nitrogen species and can be identified in most of the key steps in the pathophysiology of SE (Dousset et al 2005;Sahnoun et al 2007;Raouraoua-Boukari et al 2012).…”

“…The release of these pro-inflammatory mediators would also be implied in the genesis of the cardiorespiratory perturbations (Magalhães et al 1999;Fukuhara et al 2003). Furthermore, the inflammatory reaction observed after scorpion stings is characterized by the release of various inflammatory mediators, including cytokines, eicosanoids, reactive oxygen species, and nitric oxide (NO) (Magalhães et al 1999;De-Matos et al 2001;Fukuhara et al 2003;Hammoudi-Triki et al 2004;Raouraoua-Boukari et al 2012). The intense inflammatory response is further amplified by an intrinsic vascular compartment involving the activation of kinin-kallikrein and complement system.…”

Neuropathophysiological Effect and Immuno-Inflammatory Response Induced by Kaliotoxin of <b><i>Androctonus</i></b> Scorpion Venom

“…The pathogenesis of these disturbances is multifactorial. In previous studies, it has been reported that A. australis Hector venom and its toxins are able to induce an inflammatory response characterized by high serum levels of cytokines, nitric oxide (NO), cellular peroxidase activities [eosinophil peroxidase (EPO), myeloperoxidase (MPO)], and tissue leucocytosis [14,15,17,18]. …”