Bitis arietans Snake Venom and Kn-Ba, a Snake Venom Serine Protease, Induce the Production of Inflammatory Mediators in THP-1 Macrophages.

Ângela Alice Amadeu Megale,Felipe Raimondi Guidolin,Wilmar Dias-Da-Silva,Kemily Stephanie Godoi,Fernanda Calheta Vieira Portaro,Fabio Carlos Magnoli

doi:10.3390/toxins13120906

Abstract

Bitis arietans is a snake of medical importance found throughout sub-Saharan Africa and in savannas and pastures of Morocco and western Arabia. The effects of its venom are characterized by local and systemic alterations, such as inflammation and cardiovascular and hemostatic disturbances, which can lead to victims’ death or permanent disability. To better characterize the inflammatory process induced by this snake’s venom, the participation of eicosanoids and PAF (platelet- activating factor) in this response were demonstrated in a previous study. In addition, edema and early increased vascular permeability followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity were accompanied by the production of the eicosanoids LTB4, LTC4, TXB2, and PGE2, and local and systemic production of IL-6 and MCP-1. In this context, the present study focused on the identification of inflammatory mediators produced by human macrophages derived from THP-1 cells in response to Bitis arietans venom (BaV), and Kn-Ba, a serine protease purified from this venom. Here, we show that Kn-Ba, and even the less intensive BaV, induced the production of the cytokine TNF and the chemokines RANTES and IL-8. Only Kn-Ba was able to induce the production of IL-6, MCP-1, and IP-10, whereas PGE2 was produced only in response to BaV. Finally, the release of IL-1β in culture supernatants suggests the activation of the inflammasomes by the venom of Bitis arietans and by Kn-Ba, which will be investigated in more detail in future studies.

Highlights

The global burden of snake envenoming is estimated at around 400,000 cases/year, with 20,000 deaths/year
The present study focused on the identification of inflammatory mediators induced by Bitis arietans venom (BaV) and Kn-Ba in human macrophages differentiated from THP-1 cells (THP-1 macrophages)
Our study showed that BaV and Kn-Ba are able to induce the activation and the production of inflammatory mediators in THP-1-derived human macrophages, and this is the first suggestion that the inflammasomes may play a role in Bitis arietans envenomation

Summary

Introduction

The global burden of snake envenoming is estimated at around 400,000 cases/year, with 20,000 deaths/year. 94,000 deaths/year may occur [1]. On the African continent, more than 60% of these accidents happen in sub-Saharan Africa, of which 95% occur in rural regions, leading to about 12,000 to 32,000 deaths and more than 9000 amputations related to post-envenoming complications [1,2]. At high altitudes, and in regions with long-lasting snow seasons, venomous snake species are distributed worldwide, living naturally in intimate contact with human populations [3]. In the different global regions, the number of venomous snake species is large and varied. In the Middle East and North Africa, 17 snake species are found, and in sub-Saharan Africa, encompassing the Central, East, South, and

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