Topical Exposure to Nemopilema nomurai Venom Triggers Oedematogenic Effects: Enzymatic Contribution and Identification of Venom Metalloproteinase

Scyphozoan envenomation is featured as severe cutaneous damages due to the toxic effects of venom components released by the stinging nematocysts of a scyphozoan. However, the oedematogenic property and mechanism of scyphozoan venoms remain uninvestigated. Here, we present the oedematogenic properties of the nematocyst venom from Nemopilema nomurai (NnNV), a giant stinging scyphozoan in China, for the first time, using in vivo and in vitro models with class-specific inhibitors. NnNV was able to induce remarkable oedematogenic effects, including induction of significant oedema in the footpad and thigh of mouse, and increase in vascular permeability in the dorsal skin and kidney. Moreover, batimastat, a specific metalloproteinase inhibitor, could significantly reduce the Evan’s blue leakage in the damaged organs and attenuate paw oedema after 12 h, but exerted no influence on NnNV-induced thigh oedema. These observations suggested a considerable contribution of NnNV metalloproteinase-like components to the increased vasopermeability, and the participation was strongly suggested to be mediated by destroying the integrity of the vascular basement membrane. Moreover, partial isolation combined LC-MS/MS profiling led to identification of the protein species Nn65 with remarkable metalloproteinase activity. This study contributes to the understanding of the effector components underlying the cutaneous damages induced by scyphozoan stings.