Inflammatory Effects of Bothrops Phospholipases A2: Mechanisms Involved in Biosynthesis of Lipid Mediators and Lipid Accumulation

Abstract

Phospholipases A2s (PLA2s) constitute one of the major protein groups present in the venoms of viperid and crotalid snakes. Snake venom PLA2s (svPLA2s) exhibit a remarkable functional diversity, as they have been described to induce a myriad of toxic effects. Local inflammation is an important characteristic of snakebite envenomation inflicted by viperid and crotalid species and diverse svPLA2s have been studied for their proinflammatory properties. Moreover, based on their molecular, structural, and functional properties, the viperid svPLA2s are classified into the group IIA secreted PLA2s, which encompasses mammalian inflammatory sPLA2s. Thus, research on svPLA2s has attained paramount importance for better understanding the role of this class of enzymes in snake envenomation and the participation of GIIA sPLA2s in pathophysiological conditions and for the development of new therapeutic agents. In this review, we highlight studies that have identified the inflammatory activities of svPLA2s, in particular, those from Bothrops genus snakes, which are major medically important snakes in Latin America, and we describe recent advances in our collective understanding of the mechanisms underlying their inflammatory effects. We also discuss studies that dissect the action of these venom enzymes in inflammatory cells focusing on molecular mechanisms and signaling pathways involved in the biosynthesis of lipid mediators and lipid accumulation in immunocompetent cells.

Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?

“…A mechanism analogous to this has also been hypothesized for proteins that form amyloid oligomers, but, in recent years, an alternative hypothesis has emerged: that condensates of these proteins on the plasma membrane may activate harmful intracellular signaling. This alternative hypothesis could also explain the action of snake sPLAs, which activate various signal cascades, thus triggering inflammatory responses and, at high concentrations, even cell death [ 84 , 85 ]. Several venom sPLA2s are internalized and, similar to human sPLA2s, localized in the nuclear or paranuclear zone [ 68 , 86 , 87 ], where they can alter molecular complexes involved in lipid metabolism and, for instance, cause excess production of reactive oxygen species or toxic lipid derivatives.…”

Review of the Mechanisms of Snake Venom Induced Pain: It’s All about Location, Location, Location

“…The first paradigm of location concerns the molecular site of action that causes pain. The molecular composition of venom obtained from snakes can be remarkably complex, composed of biogenic amines, enzymes, peptides, and other substances to incapacitate their prey [1][2][3][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]. The reader is referred to a few recent excellent reviews for greater detail [57][58][59]62].…”

“…The reader is referred to a few recent excellent reviews for greater detail [57][58][59]62]. Examples of such compounds include proteins, small molecular weight, non-enzymatic compounds, serine proteases, metalloproteinases, phospholipase A 2 , and 3-finger toxins [1][2][3][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72]. These venom components or their enzymatic byproducts interact with a variety of receptors on Aδ and C pain fibers as recently reviewed [58][59][60].…”

“…While these snake venom enzymes are perhaps most feared for their properties as preganglionic neurotoxins (β-neurotoxins) that inflict apneic death [1,[57][58][59], they also cause edema, tissue injury and, critically, pain [57][58][59]62,[72][73][74][75][76]. PLA 2 activity catalyzes phospholipids in the bite site and beyond after release into the circulation, resulting in formation of bradykinin, biogenic amines, prostaglandins, and other compounds that inflict pain [57,58,62,[72][73][74][75][76]. For example, PLA 2 isolated from Crotalus durissus species venom has been demonstrated to activate C fibers, resulting in the release of substance P, mast cell degranulation, and finally, release of histamine and serotonin [63].…”

Celebrating 120 Years of Butantan Institute Contributions for Toxinology

“…We selected 19 original articles and 4 reviews approaching several points of Toxinology. The venom of snakes was approached in different aspects as the structural and functional variability in the composition of venoms from individual snakes [1], the mechanisms of action of whole venoms [2,3], the mechanisms of action of individual components as crotoxin [4], phospholipases A2 [5], metalloproteinases [6][7][8], and the oral immunity induced by whole venoms and their components [9]. Venoms from other animals are also reported; the venoms of centipedes [10], scorpions [11,12], fishes [13,14], and caterpillars [15], including microbial toxins [16].…”