The kiss of (cell) death: can venom-induced immune response contribute to dermal necrosis following arthropod envenomations?

Introduction: Snakes, insects, arachnids and myriapods have been linked to necrosis following envenomation. However, the pathways involved in arthropod venom-induced necrosis remain a highly controversial topic among toxinologists, clinicians and the public. On the one hand, clinicians report on alleged envenomations based on symptoms and the victims' information. On the other hand, toxinologists and zoologists argue that symptoms are incompatible with the known venom activity of target species. This review draws from the literature on arthropod envenomations, snakebite, and inflammatory processes to suggest that envenomation by a range of organisms might trigger an intense inflammatory cascade that ultimately lead to necrosis. If confirmed, these processes would have important implications for the treatment of venom-induced necrosis. Objectives: To describe two inflammatory pathways of regulated necrosis, tumour necrosis factor (necroptosis) and Neutrophil Extracellular Traps (NETosis); to discuss existing knowledge about snake venom and arachnid-induced necrosis demonstrating the involvement of tumour necrosis factor and neutrophils in the development of tissue necrosis following envenomation and to contribute to the understanding of venom-induced necrosis by arthropods and provide clinicians with an insight into little known inflammatory processes which may occur post envenomation. Methods: ISI Web of Science databases were searched using the terms "spider bite necrosis", "arthropod envenomation necrosis", "venom necrosis", "venom immune response", "loxoscelism", "arachnidism", "necroptosis venom", "necroptosis dermatitis", "tumour necrosis factor TNF venom", "scorpionism", "scolopendrism", "centipede necrosis", "NETosis venom", "NETosis necrosis". Searches produced 1737 non-duplicate citations of which 74 were considered relevant to this manuscript. Non-peer-reviewed sources or absence of voucher material identifying the organism were excluded. What is necrosis? Necrosis is the breakdown of cell membrane integrity followed by inflowing extracellular fluid, organelle swelling and the release of proteolytic enzymes into the cytosol. Necrosis was historically considered an unregulated process; however, recent studies demonstrate that necrosis can also be a programmed event resulting from a controlled immune response (necroptosis). Tumour necrosis factor and the necroptosis pathway: Tumour necrosis factor is a pro-inflammatory cytokine involved in regulating immune response, inflammation and cell death/survival. The pro-inflammatory cytokine TNF-α participates in the development of necrosis after envenomation by vipers. Treatment with TNF-α-antibodies may significantly reduce the manifestation of necrosis. Neutrophil Extracellular Traps and the NETosis pathway: The process by which neutrophils discharge a mesh of DNA strands in the extracellular matrix to entangle ("trap") pathogens, preventing them from disseminating. Neutrophil Extracellular Traps have been recently described as important in venom-induced necrosis. Trapped venom accumulates at the bite site, resulting in significant localized necrosis. Arthropod venom driving necrosis: Insects, myriapods and arachnids can induce necrosis following envenomation. So far, the processes involved have only been investigated in two arachnids: Loxosceles spp. (recluse spiders) and Hemiscorpius lepturus (scorpion). Loxosceles venom contains phospholipases D which hydrolyse sphingomyelin, resulting in lysis of muscle fibers. Subsequently liberated ceramides act as intermediaries that regulate TNF-α and recruit neutrophils. Experiments show that immune-deficient mice injected with Loxosceles venom experience less venom-induced inflammatory response and survive longer than control mice. Necrosis following Hemiscorpius lepturus stings correlates with elevated concentrations of TNF-α. These observations suggest that necrosis may be indirectly triggered or worsened by pathways of regulated necrosis in addition to necrotic venom compounds. Conclusions: Envenomation often induce an intense inflammatory cascade, which under certain circumstances may produce necrotic lesions independently from direct venom activity. This could explain the inconsistent and circumstantial occurrence of necrosis following envenomation by a range of organisms. Future research should focus on identifying pathways to regulated necrosis following envenomation and determining more efficient ways to manage inflammation. We suggest that clinicians should consider the victim's immune response as an integral part of the envenomation syndrome.