Study of the molecular mechanisms involved in the immunomodulation exerted by crotoxin and phospholipase A2 from Crotalus durissus terrificus venom

Abstract

Animal venoms have been studied aiming to elucidate the pathophysiology of the envenomation as well as the identification of the molecules with therapeutic potential. The envenomation by Crotalus durissus terrificus rattlesnake, unlike those induced by many others snakes, is characterized by discrete local reaction and pronunciated systemic effects. It has been shown that the main toxin (crotoxin-CTX) or its subunits: crotapotin (CA) and phospholipase A2 (PLA2-CB) do not induce proinflammatory action and are able to suppress some parameters of the immune response. Thus, these molecules have been studied as immunomodulatory tools. We verified that CTX and CB are able to inhibit the heterologous immune response and experimental colitis in mice. Since Dendritic Cell (DC) plays a crucial role in the induction of the adaptive immunity and/or maintenance of the tolerance, we analyzed the effect of CTX and CB on this cell. We verified that both molecules inhibit the DC maturation induced by LPS and also promote the secretion of prostaglandina E2 (PGE2), lipoxin A4 (LXA4), IL-10 and TGF-² expression by DC. In addition, we demonstrated the involviment of Formyl Peptide Receptors (FPRs) in this effect. Despite these data, the mechanism involved in the CTX and CB effect on DC and the elicitation of the specific-adaptive response is not elucidated. Thus, we aim to study the role of LXA4, IL-10 in the effect of CTX and CB on DCs activity. We also intend to evaluate the expression of SOCs1, 2 and 3 on DCs incubated with CTX or CB, as well as the involvement of mTOR and AMPK pathways in the effect of CTX and CB on DCs. With this study we intend to contribute to the clarification of the mechanisms that regulate the functional activity of DCs using CTX and CB and thus, in the relationship between components of the innate and adaptive immune system. (AU)