​Distinct Phospholipases A2 from Bothrops jararacussu venom drive the Variability of DAMP-Mediated Leukocyte Infiltration

B. jararacussu envenomation causes severe local myonecrosis driven mainly by  phospholipases A2 (PLA_2s): Bothropstoxin-I (BthTX-I) and -II (BthTX-II). Despite distinct catalytic profiles, both induce myotoxicity via unclear mechanisms, triggering DAMP release, leukocyte recruitment and inflammation. Limited antivenom efficacy against local effects and clinical variability in muscle regeneration suggest that host inflammatory profiles influence repair outcomes. We aimed to evaluate how these PLA_2s modulate muscle-immune response and how host inflammatory responses and NLRP3 activation impacts tissue repair variability. For this, it was used AIRmax and AIRmin mice, selected for divergent acute inflammation, and NLRP3-incompetent (AIRmin^PyT/T). BthTX-I and II were isolated via ion-exchange chromatography. Phospholipasic assay (NOB) confirmed high catalytic activity of BthTX-II, unlike BthTX-I. In myotubes C2C12, both toxins induced IL-6 and MCP-1, but not IL-1β, after 24h. BthTX-I induced higher IL-6 secretion than BthTX-II, while their combination enhanced MCP-1. Proteomics analysis (LC-MS/MS) of cell lysates revealed differential expression of inflammatory and muscle proteins, indicating distinct pathway activation. In vivo cell recruitment at 24h of toxins injection was evaluated by FACS. Toxins caused distinct leukocyte recruitment, whereas AIRmax mice showed higher neutrophil infiltration after BthTX-II than BthTX-I, and more leukocyte recruitment than AIRmin. AIRmin^PyT/T mice lacked Mac-1 integrin expression across conditions, explaining reduced cell migration. Our data highlight that BthTX-I/II cause direct muscle damage, triggering DAMPs and cytokines release, contributing to a muscle-immune crosstalk. This scenario orchestrates leukocyte recruitment across different inflammatory profiles and shapes immune response and tissue repair variability (CEUAIB 7586170625).