Modulation of Adhesion Molecules Expression by Different Metalloproteases Isolated from Bothrops Snakes

Abstract

Snake venom metalloproteinases (SVMP) are involved in local inflammatory reactions observed after snakebites. Based on domain composition, they are classified as PI (pro-domain + proteolytic domain), PII (PI + disintegrin-like domains), or PIII (PII + cysteine-rich domains). Here, we studied the role of different SVMPs domains in inducing the expression of adhesion molecules at the microcirculation of the cremaster muscle of mice. We used Jararhagin (Jar)—a PIII SVMP with intense hemorrhagic activity, and Jar-C—a Jar devoid of the catalytic domain, with no hemorrhagic activity, both isolated from B. jararaca venom and BnP-1—a weakly hemorrhagic P1 SVMP from B. neuwiedi venom. Toxins (0.5 µg) or PBS (100 µL) were injected into the scrotum of mice, and 2, 4, or 24 h later, the protein and gene expression of CD54 and CD31 in the endothelium, and integrins (CD11a and CD11b), expressed in leukocytes were evaluated. Toxins induced significant increases in CD54, CD11a, and CD11b at the initial time and a time-related increase in CD31 expression. In conclusion, our results suggest that, despite differences in hemorrhagic activities and domain composition of the SVMPs used in this study, they behave similarly to the induction of expression of adhesion molecules that promote leukocyte recruitment.

Understanding Local Reactions Induced by Bothrops jararaca Snake Venom: Role of Inflammatory Mediators in Leukocyte-Endothelium Interaction

“…Although celecoxib inhibited adhesion and migration events after 2 hours and 24 hours, respectively, it had no role in inhibiting migrated cells after 2 hours of exposure to the venom (Figures 3A and 3B). The initial times of the leukocyte-endothelium interaction are predominantly cell adhesion, and in the later times, there is migration to the extravascular space since these interactions occur because of the expression of adhesion molecules that have sequential and orchestrated kinetics [33,34]. Other inhibitors that have been found effective in preventing microcirculation changes are those targeting the nitric oxide pathway.…”

“…Bothrops venoms can induce inflammatory responses, activating signaling pathways that culminate in the transcription of inflammatory genes such as cytokines and eicosanoids, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6), with consequent release of vasoactive substances and consequent increase in vascular permeability, activation of endothelial cells, expression of adhesion molecules, which will trigger capture, rolling, firm adherence and cell migration [15,[34][35][36][37][38].…”

Altered RNome expression in Murine Gastrocnemius Muscle following Exposure to Jararhagin, a Metalloproteinase from Bothrops jararaca Venom

“…This, along with the action of hemodynamic biophysical forces, can cause a mechanical disruption of BM structure, leading to local bleeding and, in some cases, a systemic effect (bleeding) [ 2 , 14 ]. The proinflammatory in vivo response induced by jararhagin is characterized by an increase in the adhesion and migration of leukocytes [ 15 ] with polymorphonuclear and mononuclear cell infiltrates [ 16 ]. The proinflammatory cytokines, TNF-α, IL-6, and IL-1β released in the local tissue damage (LTD) [ 17 ], followed by mechanical hyperalgesia with the involvement of the proinflammatory cytokines TNF-α and IL-1β, and the nuclear transcription factor “NFkB” [ 18 ].…”

Altered RNome expression in Murine Gastrocnemius Muscle Following Exposure to Jararhagin, a Metalloproteinase from Bothrops Jararaca Venom

“…This, along with the action of hemodynamic biophysical forces, can cause a mechanical disruption of BM structure, leading to local bleeding and, in some cases, a systemic effect (bleeding) [2,14]. The pro-inflammatory in vivo response induced by jararhagin is characterized by an increase in the adhesion and migration of leukocytes [15] with polymorphonucelar and mononuclear cells infiltrate [16] pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β released in the local tissue damaged (LTD) [17] followed by mechanical hyperalgesia with the involvement of pro-inflammatory cytokines TNF-α and IL-1β, and nuclear transcription factor NFkB [18]. The chronic administration of jararhagin in the in vivo mouse sponge model demonstrate that this SVMP can modulate inflammatory angiogenesis, increasing inflammatory markers, as chemokines CXCL-1 and CCL2 and cytokine TNF-α, promoting neutrophil, and macrophage activation.…”