ABSTRACT
Several studies have been carried out with venom from sting and mucus of stingrays of marine or fluvial environments to compare the toxicity of their venom. However, studies demonstrating the existence of the influence of both sex and the maturation stage of stingrays on the variability of the toxic effects of venom are still scarce. Here, we investigated whether the sex and/or the stage maturation of the Potamotrygon rex stingray influence the toxic capacity of the venom to develop acute inflammation in mice. We carried out the main toxic activities in mice using venom from female or male of young and adult stingrays. Our results described here show that the nociception is mainly induced by venom from young female stingrays. In contrast, we observed the action of venom from both sex of adult stingrays in the induction of exudative phase of inflammatory process, including vascular leakage and neutrophil infiltration. Our data illustrate that the composition of the venom of P. rex is influenced by the stage of maturity of the stingray, modulating the production of peptides and proteins capable of acting on leukocytes-endothelial interactions and favoring neutrophil infiltration to the damage tissue.
ABSTRACT
Several studies have been carried out with venom from sting and mucus of stingrays of marine or fluvial environments to compare the toxicity of their venom. However, studies demonstrating the existence of the influence of both sex and the maturation stage of stingrays on the variability of the toxic effects of venom are still scarce. Here, we investigated whether the sex and/or the stage maturation of the Potamotrygon rex stingray influence the toxic capacity of the venom to develop acute inflammation in mice. We carried out the main toxic activities in mice using venom from female or male of young and adult stingrays. Our results described here show that the nociception is mainly induced by venom from young female stingrays. In contrast, we observed the action of venom from both sex of adult stingrays in the induction of exudative phase of inflammatory process, including vascular leakage and neutrophil infiltration. Our data illustrate that the composition of the venom of P. rex is influenced by the stage of maturity of the stingray, modulating the production of peptides and proteins capable of acting on leukocytes-endothelial interactions and favoring neutrophil infiltration to the damage tissue.
ABSTRACT
One of the hallmarks of acute inflammation is neutrophil infiltration of tissues. We investigated molecular mechanisms implicated in acute neutrophilic inflammation induced by the venom of a freshwater stingray (Potamotrygon cf. henlei) in mice. Ray venom induced early mobilization of neutrophil in the microvasculature of cremaster mice and infiltration of the peritoneal cavity 2 hours after injury, in a dose-response manner. IL-1 beta, IL-6, TNF-alpha, and KC were produced. The neutrophilic infiltration did not occur in mice with ST2 receptor and MyD88 adapters neutralized, or in those with PI3K and p38 MAPK signaling blocked. Drastic reduction of neutrophil infiltration to peritoneal cavities was observed in ST2(-/-), TLR2/TLR4(-/-), MyD88(-/-), TRIF-/- and IL-17A(-/-) mice, and a partial reduction was observed in IL-18R(-/-) mice. Mast cell Kit W(sh)/W(sh)-, AHR-, NLRP3-, ICE-, IL-1 beta-, P2RX7-, CD39-, IL-17RA-, and TBX21 KO mice retain the ability to induce neutrophilia in peritoneal cavity after ray venom injection. IL- 6 and TNF-alpha alone were insufficient for promote neutrophilia in the absence of ST2 signaling. Finally, abundant production of IL-33 by cardiomyocytes was observed. These results refine our understanding of the importance of the IL-33/ST2 axis and IL-33-producing cardiomyocytes in the early acute neutrophilia induced by freshwater stingray venoms.
