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A C-type lectin induces NLRP3 inflammasome activation via TLR4 interaction in human peripheral blood mononuclear cells

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Abstract

Lectins are a large group of proteins found in many snake venoms. BjcuL is a C-type lectin from Bothrops jararacussu snake venom that does not present cytotoxicity action on human peripheral blood mononuclear cells (PBMCs) at concentrations of 5 and 10 μg/mL. BjcuL demonstrates an immunomodulatory role in PBMCs with the production of pro- and anti-inflammatory cytokines (IL-2, IL-10, IFN-γ, IL-6, TNF-α, and IL-17) in addition to stimulate T cells to produce reactive oxygen species (ROS) that could play a role in the acute inflammatory reaction observed in the victims. Inflammasomes are an essential arm in cells of innate immunity to detect and sense a range of endogenous or exogenous, sterile, or infectious stimuli to elicit cellular responses and effector mechanisms. NLRP3 inflammasome is a significant target for this study, because the lectin is responsible for leukocyte activation stimulating the release of inflammatory mediators, which results in dynamic cellular responses to remove the detrimental process to the body in snakebites. Thus, this study aimed to investigate how isolated BjcuL from B. jararacussu venom affects NLRP3 inflammasome activation on PBMCs. For this, the cells were isolated by density gradient and incubated with BjcuL at different periods and concentrations for the evaluation of the activation of the NLRP3 inflammasome through gene and protein expressions of ASC, CASPASE-1, and NLRP3 by RT-qPCR, Western blot, and immunofluorescence, as well as the participation of Toll-like receptor 4 (TLR4) and ROS in the IL-1β production, a product resultant of the NLRP3 inflammasome activation. Herein, BjcuL interacts with TLR4 as demonstrated by in vitro and in silico studies and induces cytokines release via NF-κB signaling. By genic and protein expression assays, BjcuL activates NLRP3 inflammasome, and the pharmacological modulation with LPS-RS, an antagonist of TLR4; LPS-SM, an agonist of TLR4; MCC950, a specific NLRP3 inhibitor, and rotenone, an inhibitor of mitochondrial ROS, confirmed the participation of TLR4 and ROS in the NLRP3 inflammasome activation and IL-1β liberation. The effects of BjcuL on the regulation and activation of the NLRP3 inflammasome complex via TLR4 activation with ROS participation may be determinant for the development of the inflammatory local effects seen in snakebite victims. In addition, in silico together with in vitro studies provide information that may be useful in the rational design of TLR agonists as well as new adjuvants for immunomodulatory therapy.

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Data availability

Data are available on request from the corresponding author. The data that support the findings of this study are available on request from the corresponding author Juliana P. Zuliani. The data are not publicly available due to state restrictions, and them containing information that could compromise research participant privacy/consent.

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Funding

The authors express their gratitude to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado de Rondônia (FAPERO) for the financial support. The authors would like to thank the Network Technological Platforms from FIOCRUZ, for the support and financing of the services provided by the Flow Cytometry and, Bioprospecting and Molecular Interaction facilities/FIOCRUZ-Rondonia. The authors would also like to Msc. Braz Junior Campos Farias for technical assistance. This study was supported by grants (428774/2016-4 and 311696/2021-0) from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Juliana Pavan Zuliani was a recipient of productivity grants 306672/2014-6 and 311696/2021-0 from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Yoda Janaína Ikenohuchi was the beneficiary of CAPES by Master fellowship.

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Authors and Affiliations

  1. Laboratory of Cellular Immunology Applied to Health, Oswaldo Cruz Foundation, FIOCRUZ Rondônia, Rua da Beira, 7671 BR364, Km 3.5, Porto Velho, RO, CEP 76812-245, Brazil

    Yoda Janaina Ikenohuchi, Milena Daniela Souza Silva, Cristina Matiele Alves Rego, Sulamita da Silva Setúbal, Alex Augusto Ferreira e Ferreira, Charles Nunes Boeno, Hallison Mota Santana, Kátia Paula Felipin, Mauro Valentino Paloschi & Juliana Pavan Zuliani

  2. Department of Physics and Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, SP, Brazil

    Aleff Ferreira Francisco & Marcos Roberto de Mattos Fontes

  3. Laboratory of Biotechnology of Proteins and Bioactive Compounds Applied to Health (LABIOPROT) and National Institute of Science and Technology in Epidemiology of the Occidental Amazonia (INCT-EPIAMO), Oswaldo Cruz Foundation, FIOCRUZ Rondônia, Porto Velho, RO, Brazil

    Aleff Ferreira Francisco, Anderson Maciel de Lima & Andreimar Martins Soares

  4. Institute for Advance Studies of the Sea (IEAMAR), São Paulo State University, UNESP, São Vicente, SP, Brazil

    Marcos Roberto de Mattos Fontes

  5. Department of Medicine, Federal University of Rondônia, UNIR, Porto Velho, RO, Brazil

    Juliana Pavan Zuliani

Authors
  1. Yoda Janaina Ikenohuchi
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  2. Milena Daniela Souza Silva
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  3. Cristina Matiele Alves Rego
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  14. Juliana Pavan Zuliani
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Contributions

JPZ and YJI designed the study; YJI, MDSS, CMAR, SSS, AFF, CNB, HMS, KPF, and MVP performed the experiments; AFF and MRMF performed the bioinformatics experiments; YJI, HMS, CMAR, MDSS, KPF, MVP, CNB, and SSS collected and analyzed the data; JPZ, SSS, and AMS provided reagents; JPZ, YJI, MVP, AFF, AFF, and MRMF wrote the manuscript; MVP formatted the figures. All authors discuss the results and comment on the manuscript at all stages.

Corresponding author

Correspondence to Juliana Pavan Zuliani.

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Ikenohuchi, Y.J., Silva, M.D.S., Rego, C.M.A. et al. A C-type lectin induces NLRP3 inflammasome activation via TLR4 interaction in human peripheral blood mononuclear cells. Cell. Mol. Life Sci. 80, 188 (2023). https://doi.org/10.1007/s00018-023-04839-z

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  • DOI: https://doi.org/10.1007/s00018-023-04839-z

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