**3. Conclusions**

The existing literature demonstrates that the svPLA2s trigger a cascade of inflammatory events including edema formation, leukocyte recruitment into tissues, release of a complex network of inflammatory mediators, and increased oxidative stress in experimental animal models that mimic the inflammatory responses elicited by viperid snake

venoms, especially those from the *Bothrops* genus, in the victims. The catalytic activity of the svPLA2s is not strictly required by these proteins for the triggering of all the inflammatory responses, since the catalytically inactive Lys49 PLA2 variants can display inflammatory events that are qualitatively similar to those of Asp49 PLA2s. In addition to cell migration, the svPLA2s can activate distinct functions of immunocompetent cells that include phagocytosis, the respiratory burst, NET formation, production of cytokines, chemokines and multiple reactive cleavage products such as lysophospholipids, polyunsaturated fatty acids and eicosanoids, as well as formation of LDs. The highly complex network of mediators, particularly lipid mediators, modulates a variety of inflammatory events triggered by this class of snake venom toxins. The effects triggered by svPLA2s in inflammatory cells that lead to generation of lipid mediators has been associated with the activation of distinct signaling pathways of inflammatory kinase proteins by mechanisms dependent and independent of NF-kB. Moreover, the inflammatory response elicited by svPLA2s in leukocytes also involves upregulation of PRRs of innate immune response, the crosstalk between the svPLA2 and intracellular PLA2s, and upregulation of factors implicated in lipid homeostasis. Although much has been learned regarding the inflammatory actions of svPLA2s, many knowledge gaps still exist and need to be addressed. There is still considerable work to be done before we fully understand the complex interactions that occur among svPLA2s and immunocompetent cells and tissues that lead to inflammation. The cell acceptors and/or receptors involved in the actions of svPLA2s in these cells and the signaling pathways elicited and how they interact with each other remain to be clarified. In addition, the actual types and subtypes of receptors activated by the principal mediators produced by svPLA2s and the mechanisms involved in coupling between the svPLA2s and endogenous PLA2s have yet to be investigated. Recently, the stimulatory activity of a svPLA2 on adipose tissue cells leading to increased biosynthesis of PGE2 and other inflammatory mediators including adipokines was demonstrated. This information offers new directions for investigating the actions triggered by svPLA2s and mammalian GIIA sPLA2 and gives insights into the potential role of the adipocytes as target cells for viperid snake venoms. Finally, a deeper and comprehensive understanding of the mechanisms underlying the inflammatory actions of svPLA2s will give new insights into (i) the actions of group IIA sPLA2s in diseases related to lipid imbalance and inflammation and (ii) a better understanding of the pathophysiology of *Bothrops* envenomation. Within this frame, the acquired knowledge might pave the way for the development of novel therapeutic approaches aimed at counteracting the prominent inflammation caused by *Bothrops* snakebite envenoming.

**Author Contributions:** Conceptualization, C.T., V.M., E.L. and C.M.F.; writing—original draft, C.T., V.M., E.L., C.M.F., P.M.J. and R.M.-M.; writing—review and editing, C.T., V.M., E.L., C.M.F., P.M.J. and R.M.-M.; visualization, V.M. and R.M.-M.; supervision, C.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Fundação Butantan, São Paulo, Brazil. E.L. is a recipient of a postdoctural fellowship from Coordenação de Aperfeicçoamento de Pessoal de Nível Superior (CAPES). C.T. is a recipient of a Conselho Nacional de Desenvolvimento Científico e Tecnológico fellowship (PQ-CNPq), grant number 310930/201.7. R.M.M. is recipient of a doctoral fellowship from Fundação Butantan, grant FB 001/0708/003.434/2021.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
