Delayed local inflammatory response induced by Thalassophryne nattereri venom is related to extracellular matrix degradation

Abstract

Symptoms evoked by Thalassophryne nattereri fish envenomation include local oedema, severe pain and intense necrosis with strikingly inefficient healing, continuing for several weeks or months. Investigations carried out in our laboratory showed that, in the venom-induced acute inflammation, thrombosis in venules and constrictions in arterioles were highly visible, in contrast to a notable lack of inflammatory cell. Nevertheless, the reason that the venom toxins favour delayed local inflammatory response is poorly defined. In this study, we analysed the movement of leucocytes after T. nattereri venom injection in the intraplantar region of Swiss mice, the production of pro-inflammatory mediators and the venom potential to elicit matrix metalloproteinase production and extracellular matrix degradation. Total absence of mononuclear and neutrophil influx was observed until 14 days, but the venom stimulates pro-inflammatory mediator secretion. Matrix metalloproteinases (MMP)-2 and MMP-9 were detected in greater quantities, accompanied by tissue degradation of collagenous fibre. An influx of mononuclear cells was noted very late and at this time the levels of IL-6, IL-1beta and MMP-2 remained high. Additionally, the action of venom on the cytoskeletal organization was assessed in vitro. Swift F-actin disruption and subsequent loss of focal adhesion was noted. Collectively these findings show that the altered specific interaction cell-matrix during the inflammatory process creates an inadequate environment for infiltration of inflammatory cells.

Role of interplay between IL-4 and IFN-γ in the in regulating M1 macrophage polarization induced by Nattectin

“…Fish have evolved natural immune modulators such as galectins and C-type lectins within tissues and cells associated with host defense functions against microbial pathogens. The venom of T. nattereri have been widely investigated in relation to different aspects [21][22][23][24][25][26][27][28][29][30][31] and recently, a 15 kDa monomeric toxin belonging to the family of C-type lectins denominated Nattectin was identified and characterized [7,8,32,33].…”

Bioactive Components in Fish Venoms

“…Interestingly, where T. maculosa venom was found to cause venular stasis [ 100 ], T. nattereri venom was shown to cause arteriolar stasis, along with increased vascular permeability and thrombosis [ 92 ]. Parejo-Santos et al [ 115 ] showed that the venom altered the extracellular matrix in such a way as to create an inhospitable environment for the inflammatory cells that would promote healing, thus explaining the chronic, slow healing injuries that result from T. nattereri stings and can lead to necrosis. Representative drugs for both steroidal and non-steroidal anit-inflammatory agents failed to reduce edema from T. nattereri venom, as did inhibitors of serotonin and nitric oxide synthase [ 49 ].…”

Thalassophryne nattereri fish venom: from the envenoming to the understanding of the immune system

“…Moreover, absence of leukocytes infiltration in the intraplantar region of footpad of mice after venom application was also reported [ 15 ]. Moreover, Pareja-Santos et al [ 16 ] showed that T. nattereri venom alters the extracellular matrix structure of mouse footpad tissue by the activation of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), and it decreases collagen fiber production during the healing phase. It was also shown that the venom affects the cytoskeleton organization and pseudopodia formation of epithelial cells in in vitro system.…”