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Abstract
Background: The opening of pannexin1 channels is considered as a key event in inflammation. Pannexin1 channel-mediated release of adenosine triphosphate triggers inflammasome signaling and activation of immune cells. By doing so, pannexin1 channels play an important role in several inflammatory diseases. Although pannexin1 channel inhibition could represent a novel clinical strategy for treatment of inflammatory disorders, therapeutic pannexin1 channel targeting is impeded by the lack of specific, potent and/or in vivo-applicable inhibitors. The goal of this study is to generate nanobody-based inhibitors of pannexin1 channels.
Results: Pannexin1-targeting nanobodies were developed as potential new pannexin1 channel inhibitors. We identified 3 cross-reactive nanobodies that showed affinity for both murine and human pannexin1 proteins. Flow cytometry experiments revealed binding capacities in the nanomolar range. Moreover, the pannexin1-targeting nanobodies were found to block pannexin1 channel-mediated release of adenosine triphosphate. The pannexin1-targeting nanobodies were also demonstrated to display anti-inflammatory effects in vitro through reduction of interleukin 1 beta amounts. This anti-inflammatory outcome was reproduced in vivo using a human-relevant mouse model of acute liver disease relying on acetaminophen overdosing. More specifically, the pannexin1-targeting nanobodies lowered serum levels of inflammatory cytokines and diminished liver damage. These effects were linked with alteration of the expression of several NLRP3 inflammasome components.
Conclusions: This study introduced for the first time specific, potent and in vivo-applicable nanobody-based inhibitors of pannexin1 channels. As demonstrated for the case of liver disease, the pannexin1-targeting nanobodies hold great promise as anti-inflammatory agents, yet this should be further tested for extrahepatic inflammatory disorders. Moreover, the pannexin1-targeting nanobodies represent novel tools for fundamental research regarding the role of pannexin1 channels in pathological and physiological processes.
Results: Pannexin1-targeting nanobodies were developed as potential new pannexin1 channel inhibitors. We identified 3 cross-reactive nanobodies that showed affinity for both murine and human pannexin1 proteins. Flow cytometry experiments revealed binding capacities in the nanomolar range. Moreover, the pannexin1-targeting nanobodies were found to block pannexin1 channel-mediated release of adenosine triphosphate. The pannexin1-targeting nanobodies were also demonstrated to display anti-inflammatory effects in vitro through reduction of interleukin 1 beta amounts. This anti-inflammatory outcome was reproduced in vivo using a human-relevant mouse model of acute liver disease relying on acetaminophen overdosing. More specifically, the pannexin1-targeting nanobodies lowered serum levels of inflammatory cytokines and diminished liver damage. These effects were linked with alteration of the expression of several NLRP3 inflammasome components.
Conclusions: This study introduced for the first time specific, potent and in vivo-applicable nanobody-based inhibitors of pannexin1 channels. As demonstrated for the case of liver disease, the pannexin1-targeting nanobodies hold great promise as anti-inflammatory agents, yet this should be further tested for extrahepatic inflammatory disorders. Moreover, the pannexin1-targeting nanobodies represent novel tools for fundamental research regarding the role of pannexin1 channels in pathological and physiological processes.
Original language | English |
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Article number | 371 |
Pages (from-to) | 371 |
Number of pages | 20 |
Journal | Journal of Nanobiotechnology |
Volume | 21 |
Issue number | 1 |
DOIs | |
Publication status | Published - 11 Oct 2023 |
Bibliographical note
Funding Information:This work was financially supported by the European Research Council (Proof-of-Concept grant 861913), the European Future and Emerging Technologies program (grant 858014), the Research Foundation Flanders-Belgium (grants G012318N, G020018N and G0F7219N), a Lead Agency grant of the Research Foundation Flanders-Belgium and the Swiss National Science Foundation (310030E-176050), the Methusalem program of the Flemish Government, the University Hospital of the Vrije Universiteit Brussel-Belgium (Scientific Fund Willy Gepts) and the Strategic Research Program SRP50. TDG is funded by a post-doctoral fellowship (12ZO723N) from the Research Foundation Flanders-Belgium
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
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FWOAL1070: The role of pannexin1 channels in non-alcoholic steatohepatitis: therapeutic and diagnostic relevance.
1/01/23 → 31/12/26
Project: Fundamental
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SRP83: SRP-Onderzoekszwaartepunt: ITAREG: Molecular Imaging and TArgeting of immunoREGulatory cells in Inflammatory diseases and cancer
Van Ginderachter, J., Lahoutte, T., Lahoutte, T., Van Ginderachter, J., Devoogdt, N., Raes, G., Stijlemans, B., Vincke, C. & De Groof, T.
1/11/22 → 31/10/27
Project: Fundamental
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FWOAL879: Nanobody-based inhibitors of connexin hemichannels and pannexin channels as novel therapeutics for the treatment of inflammatory hepatic and cardiovascular diseases.
Vinken, M., Muyldermans, S. & Kwak, B. R.
1/01/18 → 31/12/21
Project: Fundamental