Complement System Inhibition Modulates the Pro-Inflammatory Effects of a Snake Venom Metalloproteinase

Abstract

Envenomation by Bothrops snakes causes prominent local effects, including pain, oedema, local bleeding, blistering and necrosis, and systemic manifestations, such as hemorrhage, hypotension, shock and acute renal failure. These snake venoms are able to activate the complement system and induce the generation of anaphylatoxins, whose mechanisms include the direct cleavage of complement components by snake venom metalloproteinases and serine proteinases present in the venoms. A metalloproteinase able to activate the three complement pathways and generate active anaphylatoxins, named C-SVMP, was purified from the venom of Bothrops pirajai . Considering the inflammatory nature of Bothrops venoms and the complement-activation property of C-SVMP, in the present work, we investigated the inflammatory effects of C-SVMP in a human whole blood model. The role of the complement system in the inflammatory process and its modulation by the use of compstatin were also investigated. C-SVMP was able to activate the complement system in the whole blood model, generating C3a/C3a desArg, C5a/C5a desArg and SC5b-9. This protein was able to promote an increase in the expression of CD11b, CD14, C3aR, C5aR1, TLR2, and TLR4 markers in leukocytes. Inhibition of component C3 by compstatin significantly reduced the production of anaphylatoxins and the Terminal Complement Complex (TCC) in blood plasma treated with the toxin, as well as the expression of CD11b, C3aR, and C5aR on leukocytes. C-SVMP was able to induce increased production of the cytokines IL-1β and IL-6 and the chemokines CXCL8/IL-8, CCL2/MCP-1, and CXCL9/MIG in the human whole blood model. The addition of compstatin to the reactions caused a significant reduction in the production of IL-1β, CXCL8/IL-8, and CCL2/MCP-1 in cells treated with C-SVMP. We therefore conclude that C-SVMP is able to activate the complement system, which leads to an increase in the inflammatory process. The data obtained with the use of compstatin indicate that complement inhibition may significantly control the inflammatory process initiated by Bothrops snake venom toxins.

Snake bite associated with acute kidney injury

“…Hypovolemia and hypotension are the common harbinger of AKI associated with snake bites, and the biochemical cascades initiated by the snake venom often culminate in this single end point. Additional insults including haemoglobinuria, myoglobinuria, complement activation and reactive oxygen species play contributing roles in prolonging the duration of decreased GFR and kidney blood flow [1,44].…”

Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

“…Complement-induced cleavage products, such as C3a, are known to trigger neuroinflammation and activation of microglia expressing C3aR, which leads to the induction of chemotaxis, including proinflammatory cytokine production [30]. Generally, C3aR, a G-protein-coupled anaphylatoxin receptor, activates its downstream STAT3.…”

Catechin and epicatechin as an adjuvant in the therapy of hemostasis disorders induced by snake venoms

“…The activities evaluated are related to several processes, such as cell lysis, blood clotting, hemorrhage, and inflammation. [26,27] These processes result from the action of toxins that are homologous to human enzymes. Therefore, the broad spectrum of action of phenolic compounds in modulating these human enzymes is highlighted.…”