C5a-C5aR1 Axis Activation Drives Envenomation Immunopathology by the Snake Naja annulifera

Autor(es)

Silva de Franca, Felipe ^[1] ; Villas-Boas, Isadora Maria ^[1] ; Cogliati, Bruno ^[2] ; Woodruff, Trent M. ^[3] ; Reis, Edimara da Silva ^[4] ; Lambris, John D. ^[4] ; Tambourgi, Denise V. ^[1]

Afiliação do(s) autor(es)

^[1] Inst Butantan, Immunochem Lab, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Vet Med & Anim Sci, Dept Pathol, Sao Paulo - Brazil

^[3] Univ Queensland, Sch Biomed Sci, Neuroinflammat Lab, St Lucia, Qld - Australia

^[4] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA - USA

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 12, APR 15 2021.
• Citações Web of Science: 0

Resumo

Systemic complement activation drives a plethora of pathological conditions, but its role in snake envenoming remains obscure. Here, we explored complement's contribution to the physiopathogenesis of Naja annulifera envenomation. We found that N. annulifera venom promoted the generation of C3a, C4a, C5a, and the soluble Terminal Complement Complex (sTCC) mediated by the action of snake venom metalloproteinases. N. annulifera venom also induced the release of lipid mediators and chemokines in a human whole-blood model. This release was complement-mediated, since C3/C3b and C5a Receptor 1 (C5aR1) inhibition mitigated the effects. In an experimental BALB/c mouse model of envenomation, N. annulifera venom promoted lipid mediator and chemokine production, neutrophil influx, and swelling at the injection site in a C5a-C5aR1 axis-dependent manner. N. annulifera venom induced systemic complementopathy and increased interleukin and chemokine production, leukocytosis, and acute lung injury (ALI). Inhibition of C5aR1 with the cyclic peptide antagonist PMX205 rescued mice from these systemic reactions and abrogated ALI development. These data reveal hitherto unrecognized roles for complement in envenomation physiopathogenesis, making complement an interesting therapeutic target in envenomation by N. annulifera and possibly by other snake venoms. (AU)

• Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
• Beneficiário: Hugo Aguirre Armelin
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs