Biology subjects

Pedoto, A.

Publications and source records attributed to Pedoto, A..

3 recordsLinked to original sources

bioRxiv2025

Macrophage Inflammasome Activation Drives Anti-inflammatory Responses via Neutrophil-Derived ASC Speck Transfer and Gasdermin-Dependent Caspase-1 Inhibition

Inflammasomes are critical components of the innate immune system, traditionally associated with pro-inflammatory responses. While the inflammasome in macrophages has been extensively studied and linked to pyroptosis and cytokine release, the neutrophil inflammasome remains poorly understood. Neutrophil inflammasome activation drives unique outcomes such as NETosis and robust IL-1{beta} production without inducing pyroptosis. In contrast, macrophage inflammasome activation promotes pyroptosis and the release of cytokines like IL-1 and IL-18. Here, using zebrafish models of Salmonella enterica serovar Typhimurium infection and COVID-19-associated cytokine storm syndrome (CSS), we reveal opposing roles of neutrophil and macrophage inflammasomes: neutrophil inflammasomes are pro-inflammatory, whereas macrophage inflammasomes mediate anti-inflammatory responses. We show that Gasdermin E- and Ninjurin-1-mediated cell death in neutrophils releases ASC specks, which are taken up by macrophages. This transfer negatively regulates caspase-1 activity via the C-terminal domain of Gasdermin E, promoting the resolution of inflammation. To our knowledge, this is the first study to reveal the anti-inflammatory role of the macrophage inflammasome, document the in vivo transfer of ASC specks between neutrophils and macrophages, and uncover the negative feedback regulation of the inflammasome by the C-terminal domain of Gsdme. These results offer novel insights into potential therapeutic approaches for hyperinflammatory diseases like bacterial infections and COVID-19-associated CSS.

immunology↗

bioRxiv2022

A zebrafish model of COVID-19-associated cytokine storm syndrome reveals that the Spike protein signals via TLR2

Understanding the mechanism of virulence of SARS-CoV-2 and host innate immune responses are essential to develop novel therapies. One of the most studied defense mechanisms against invading pathogens, including viruses, are Toll-like receptors (TLRs). Among them, TLR3, TLR7, TLR8 and TLR9 detect different forms of viral nucleic acids in endosomal compartments, whereas TLR2 and TLR4 recognize viral structural and nonstructural proteins outside the cell. Although many different TLRs have been shown to be involved in SARS-CoV-2 infection and detection of different structural proteins, most studies have been performed in vitro and the results obtained are rather contradictory. In this study, we report using the unique advantages of the zebrafish model for in vivo imaging and gene editing that the S1 domain of the Spike protein from the Wuhan strain (S1WT) induced hyperinflammation in zebrafish larvae via a Tlr2/Myd88 signaling pathway and independently of interleukin-1{beta} production. In addition, S1WT also triggered emergency myelopoiesis, but in this case through a Tlr2/Myd88-independent signaling pathway. These results shed light on the mechanisms involved in the COVID-19-associated cytokine storm syndrome.

immunology↗

bioRxiv2022

Combination therapy targeting inflammasome and fibrogenesis alleviates inflammation and fibrosis in a zebrafish model of silicosis

Silicosis is a long-term lung disease caused by the inhalation of large amounts of crystalline silica dust. As there is no effective treatment available, patients are provided with supportive care, and some may be considered for lung transplantation. There is therefore an evident need for a better understanding of the diseases biology and for identifying new therapeutic targets and therapies. In this context, our group has developed a larval zebrafish model of silicosis by injecting silica crystals into the hindbrain ventricle, a cavity into which immune cells can be recruited and that mimics the alveolar environment of the human lung. The injection of silica crystals into this cavity led to the initiation of local and systemic immune responses driven through both TLR- and inflammasome-dependent signaling pathways, followed by fibrosis, as happens in human patients. The combination of the inflammasome inhibitor VX-765 and the antifibrotic agent pirfenidone was found to be the best therapy to alleviate both inflammation and fibrosis. The zebrafish model of silicosis developed here is a unique tool that will shed light onto the molecular mechanisms involved in the progression of this devastating disease and for identifying novel drugs that improve the quality of life of silicosis patients.

immunology↗