Inflammasome Coordinates Senescent Chronic Wound Induced by Thalassophryne nattereri Venom

Author(s)

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

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 24, n. 9, p. 20-pg., 2023-05-08.

Abstract

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)

• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/17160-6 - Investigation of the heterogeneity and cellular plasticity in chronic injury induced by Thalassophryne nattereri venom
• Grantee: Carla Lima da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/15157-0 - Evaluation of senescence involved in tissue injury induced by t. nattereri venom
• Grantee: Fabiana Franco Carvalho
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 16/17620-0 - Evaluation the role of IL-33/IL-1beta in the control of the plasticity and heterogeneity of cellular response induced by Thalassophryne nattereri venom
• Grantee: Aline Ingrid Andrade de Barros
• Support Opportunities: Scholarships in Brazil - Scientific Initiation