Soluble P-selectin rescues viper venom–induced mortality through anti-inflammatory properties and PSGL-1 pathway-mediated correction of hemostasis

Abstract

Venomous snakebites are lethal and occur frequently worldwide each year, and receiving the antivenom antibody is currently the most effective treatment. However, the specific antivenom might be unavailable in remote areas. Snakebites by Viperidae usually lead to hemorrhage and mortality if untreated. In the present study, challenges of rattlesnake (Crotalus atrox) venom markedly increased the circulating soluble P-selectin (sP-sel) level, but not P-selectin (P-sel, Selp−/−) mutants, in wild-type mice. Because sP-sel enhances coagulation through the P-selectin ligand 1 (PSGL-1, Selplg) pathway to produce tissue factor–positive microparticles, we hypothesized that increasing the plasma sP-sel level can be a self-rescue response in hosts against snake venom–mediated suppression of the coagulation system. Confirming our hypothesis, our results indicated that compared with wild-type mice, Selp−/− and Selplg−/− mice were more sensitive to rattlesnake venom. Additionally, administration of recombinant sP-sel could effectively reduce the mortality rate of mice challenged with venoms from three other Viperidae snakes. The antivenom property of sP-sel is associated with improved coagulation activity in vivo. Our data suggest that the elevation of endogenous sP-sel level is a self-protective response against venom-suppressed coagulation. The administration of recombinant sP-sel may be developed as a new strategy to treat Viperidae snakebites.

Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis

“…35 The anti-P-sel Ig showed an ameliorative effect in our previous report using a viper venom-challenged mouse model, in which anti-P-sel Ig ameliorated snake venom-induced inflammation, coagulant defects, and mortality. 36 To investigate whether the anti-inflammation property of sP-sel is also involved in the rescue, we further examined the effects of anti-P-selneutralizing antibody treatment, as both anti-P-sel-neutralizing antibodies and recombinant sP-sel suppress inflammation by blocking leukocyte infiltration to the inflamed tissues through the P-sel and P-sel ligand interaction. 35 We observed that, similar to control Ig, the anti-P-sel-neutralizing antibody did not rescue LTtreated mice ( Fig.…”

“…20,42 In addition, it is also shown that increased levels of circulating sP-sel play a protective role when mice are under hemorrhage or hypoxic stress. 36,43 Therefore, increased endogenous sP-sel levels may theoretically have a physiologic role of protecting against hemorrhage and ischemic conditions through correcting hemostasis. Moreover, increased sP-sel levels have been observed in various hemorrhagic diseases such as dengue hemorrhagic fever, 39 immune thrombocytopenia, 44,45 and subarachnoid hemorrhage 46 ; however, the role of sP-sel in these disorders remains elusive.…”

“…60,61 In this regard, treatments of sP-sel were also shown to induce an anti-inflammatory effect. 35,36 We have previously found that sP-sel treatments are also beneficial to viper venom-induced procoagulation-associated hemorrhage pathogenesis in mice, and the rescue effect on the hypercoagulation is associated with the anti-inflammatory property of sP-sel 36 Therefore, the anti-inflammation effect may also be involved in sP-sel-mediated rescue in lethal infection of anthrax spores. Because anthrax is a complex disease, and the detailed mechanism associated with sP-selmediated rescue on anthrax spore challenge is worthy of further investigation.…”

“…Chemicals were purchased from Sigma-Aldrich (St. Louis, MO). Following described previously methods, 15,16,36,62,63 polyclonal anti-P-sel Igs were obtained from recombinant P-sel-IgG-Fc fusion protein (P-sel-Fc) immunized rabbits. Anti-P-sel antibody and an isotype control Igs were purchased from BD PharMingen Taiwan (Taipei, Taiwan) and Enzo Life Sciences (Blossom Biotechnologies, Taipei, Taiwan), respectively; and P-sel-Fc was purchased from R&D Systems (Minneapolis, MN).…”

Toxin Fused with SUMO Tag: A New Expression Vector Strategy to Obtain Recombinant Venom Toxins with Easy Tag Removal inside the Bacteria

“…Snake toxins have also been expressed into E. coli and this approach has allowed the characterization of toxins with anti-thrombotic [13], anticancer [14], anti-inflammatory [15], antimicrobial activities [16] as well as fused toxins for the development of serotherapy against envenomation [17]. However, when a recombinant protein is synthesized in E. coli , the microenvironment is different from that of the original source, which may lead to protein aggregation, known as inclusion bodies [18].…”