Inflammasome Coordinates Senescent Chronic Wound Induced by Thalassophryne nattereri Venom

Autor(es)

Lima, Carla ; Andrade-Barros, Aline Ingrid ; Carvalho, Fabiana Franco ; Falcao, Maria Alice Pimentel ; Lopes-Ferreira, Monica

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 24, n. 9, p. 20-pg., 2023-05-08.

Resumo

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for an extended period of time, with delayed healing. Wound healing is a complex process characterized by the interdependent role of keratinocytes, fibroblasts, and endothelial and innate cells such as neutrophils and macrophages. Macrophages and neutrophils are actively recruited to clear debris during the inflammatory phase of wound repair, promoting the production of pro-inflammatory mediators, and in the late stage, macrophages promote tissue repair. Our hypothesis is that injury caused by T. nattereri venom (VTn) leads to senescent wounds. In this study, we provide valuable information about the mechanism(s) behind the dysregulated inflammation in wound healing induced by VTn. We demonstrate in mouse paws injected with the venom the installation of gamma H2AX/p16(Ink4a)-dependent senescence with persistent neutrophilic inflammation in the proliferation and remodeling phases. VTn induced an imbalance of M1/M2 macrophages by maintaining a high number of TNF-alpha-producing M1 macrophages in the wound but without the ability to eliminate the persistent neutrophils. Chronic neutrophilic inflammation and senescence were mediated by cytokines such as IL-1 alpha and IL-1 beta in a caspase-1- and caspase-11-dependent manner. In addition, previous blocking with anti-IL-1 alpha and anti-IL-beta neutralizing antibodies and caspase-1 (Ac YVAD-CMK) and caspase-11 (Wedelolactone) inhibitors was essential to control the pro-inflammatory activity of M1 macrophages induced by VTn injection, skewing towards an anti-inflammatory state, and was sufficient to block neutrophil recruitment and senescence. (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
• Processo FAPESP: 15/17160-6 - Investigação da heterogeneidade e da plasticidade celular na lesão crônica induzida pelo veneno de Thalassophryne nattereri
• Beneficiário: Carla Lima da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/15157-0 - Avaliação de senescência e impacto no reparo tecidual da lesão induzida pelo veneno de Thalassophryne nattereri
• Beneficiário: Fabiana Franco Carvalho
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 16/17620-0 - Avaliação do papel de IL-33/IL-1beta no controle da heterogeneidade e da plasticidade da resposta celular induzida pelo veneno de Thalassophryne nattereri
• Beneficiário: Aline Ingrid Andrade de Barros
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica