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Abstract
Over 1 million cases of scorpion stings are estimated every year, whereas current treatment is limited to antivenom serum combined with supportive therapy. Tityus serrulatus scorpion venom (TsV) is composed of diverse molecules, including toxins that induce a catecholamine storm and mediate classical symptoms of scorpion envenomation. However, the same toxins promote an intense inflammatory response coordinated by innate immune cells, such as macrophages, contributing significantly to the lung edema and mortality caused by TsV injection. Macrophages sense TsV via innate immune receptors, including TLR2, TLR4, and CD14 that promote inflammation and mortality via PGE2/cAMP/PKA/NF-κB/IL-1β axis. The scavenger receptor CD36 also recognizes TsV, but in contrast to the other receptors, it drives the production of leukotriene B4 (LTB4). This lipid mediator operates via BLT1 receptor to reduce cAMP production and consequently IL-1β release, which results in resistance to fatal outcomes of experimental scorpion envenomation. EP80317 is an hexapeptide that serves as a ligand for CD36 and features protective effects under conditions such as atherosclerosis and vascular inflammation. In this study, we evaluated the effects of EP80317 treatment during experimental scorpion envenomation. EP80317 treatment suppressed mouse peritoneal macrophage production of IL-1β, IL-6, tumor necrosis factor (TNF-α), CCL3, and PGE2 in vitro. EP80317 treatment also boosted the production of LTB4 and IL-10 in response to TsV. Importantly, EP80317 restrained lung inflammation and mortality caused by TsV in vivo. Taken together, these data indicate a strong therapeutic potential of EP80317 as a supportive treatment to control inflammation induced by scorpion envenomation.
Highlights
Scorpion envenomation affects more than 1 million subjects every year (Chippaux and Goyffon, 2008; Isbister and Bawaskar, 2014)
EP80317 mediates protective effects via CD36 (Marleau et al, 2005; Bujold et al, 2009, 2013; Harb et al, 2009; Bessi et al, 2012; Lucchi et al, 2017), a scavenger receptor that drives eicosanoid metabolism toward leukotriene B4 (LTB4) synthesis and represses inflammation and mortality caused by scorpion envenomation (Zoccal et al, 2016, 2018b)
This suggests that binding of EP80317 to CD36 could modulate LTB4 metabolism and influence the outcome of scorpion envenomation
Summary
Scorpion envenomation affects more than 1 million subjects every year (Chippaux and Goyffon, 2008; Isbister and Bawaskar, 2014). IL-1R signaling mediates activation and accumulation of neutrophils in the lung, edema, and eventually death in a mouse model of scorpion envenomation (Zoccal et al, 2016). In stark contrast to other receptors, CD36 promotes intracellular signaling that favors LTB4 release (Zoccal et al, 2018b). This eicosanoid reduces intracellular cAMP via BLT1 receptor and suppresses IL-1β production and mortality due to scorpion envenomation (Zoccal et al, 2016, 2018b). Molecular mechanisms governing responses to TsV in mouse models are strongly correlated with that of human cell responses (Zoccal et al, 2018b)
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