Inflammatory effect of Bothropstoxin-I from Bothrops jararacussu venom mediated by NLRP3 inflammasome involves ATP and P2X7 receptor

Author(s)

Raneia e Silva, Priscila Andrade ^{[1, 2]} ; de Lima, Dhemerson Souza ^[1] ; Mesquita Luiz, Joao Paulo ^{[3, 4]} ; Saraiva Camara, Niels Olsen ^[1] ; Farias Alves-Filho, Jose Carlos ^{[3, 4]} ; Pontillo, Alessandra ^[1] ; Bortoluci, Karina Ramalho ^{[5, 6]} ; Faquim-Mauro, Eliana L. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[2] Butantan Inst, Lab Immunopathol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Immunol, Sao Paulo - Brazil

^[5] Univ Fed Sao Paulo, Dept Biol Sci, Sao Paulo - Brazil

^[6] Univ Fed Sao Paulo, Ctr Cellular & Mol Therapy CTC Mol, Sao Paulo - Brazil

• Document type: Journal article
• Source: Clinical Science; v. 135, n. 5, p. 687-701, MAR 2021.
• Web of Science Citations: 0

Abstract

Muscle tissue damage is one of the local effects described in bothropic envenomations. Bothropstoxin-I (BthTX-I), from Bothrops jararacussu venom, is a K49-phospholipase A2 (PLA2) that induces a massive muscle tissue injury, and, consequently, local inflammatory reaction. The NLRP3 inflammasome is a sensor that triggers inflammation by activating caspase 1 and releasing interleukin (IL)-1 beta and/or inducing pyroptotic cell death in response to tissue damage. We, therefore, aimed to address activation of NLRP3 inflammasome by BthTX-I-associated injury and the mechanism involved in this process. Intramuscular injection of BthTX-I results in infiltration of neutrophils and macrophages in gastrocnemius muscle, which is reduced in NLRP3- and Caspase-1-deficient mice. The in vitro IL-1 beta production induced by BthTX-I in peritoneal macrophages (PMs) requires caspase 1/11, ASC and NLRP3 and is dependent on adenosine 5{''}-triphosphate (ATP)-induced K+ efflux and P2X7 receptor (P2X7R). BthTX-I induces a dramatic release of ATP from C2C12 myotubes, therefore representing the major mechanism for P2X7R-dependent inflammasome activation in macrophages. A similar result was obtained when human monocyte-derived macrophages (HMDMs) were treated with BthTX-I. These findings demonstrated the inflammatory effect of BthTX-I on muscle tissue, pointing out a role for the ATP released by damaged cells for the NLRP3 activation on macrophages, contributing to the understanding of the microenvironment of the tissue damage of the Bothrops envenomation. (AU)

• FAPESP's process: 14/09880-6 - Study activation of inflammasome by toxins isolated from Bothrops venom and modulation of immune response
• Grantee: Priscila Andrade Ranéia e Silva
• Support Opportunities: Scholarships in Brazil - Doctorate