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The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway

Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified ef...

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Autores principales: Yang, Xiaoli, Ali, Shafaqat, Zhao, Manman, Richter, Lisa, Schäfer, Vanessa, Schliehe-Diecks, Julian, Frank, Marian, Qi, Jing, Larsen, Pia-Katharina, Skerra, Jennifer, Islam, Heba, Wachtmeister, Thorsten, Alter, Christina, Huang, Anfei, Bhatia, Sanil, Köhrer, Karl, Kirschning, Carsten, Weighardt, Heike, Kalinke, Ulrich, Kalscheuer, Rainer, Uhrberg, Markus, Scheu, Stefanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024221/
https://www.ncbi.nlm.nih.gov/pubmed/35464417
http://dx.doi.org/10.3389/fimmu.2022.856230
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author Yang, Xiaoli
Ali, Shafaqat
Zhao, Manman
Richter, Lisa
Schäfer, Vanessa
Schliehe-Diecks, Julian
Frank, Marian
Qi, Jing
Larsen, Pia-Katharina
Skerra, Jennifer
Islam, Heba
Wachtmeister, Thorsten
Alter, Christina
Huang, Anfei
Bhatia, Sanil
Köhrer, Karl
Kirschning, Carsten
Weighardt, Heike
Kalinke, Ulrich
Kalscheuer, Rainer
Uhrberg, Markus
Scheu, Stefanie
author_facet Yang, Xiaoli
Ali, Shafaqat
Zhao, Manman
Richter, Lisa
Schäfer, Vanessa
Schliehe-Diecks, Julian
Frank, Marian
Qi, Jing
Larsen, Pia-Katharina
Skerra, Jennifer
Islam, Heba
Wachtmeister, Thorsten
Alter, Christina
Huang, Anfei
Bhatia, Sanil
Köhrer, Karl
Kirschning, Carsten
Weighardt, Heike
Kalinke, Ulrich
Kalscheuer, Rainer
Uhrberg, Markus
Scheu, Stefanie
author_sort Yang, Xiaoli
collection PubMed
description Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte–macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFNβ production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-κB activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.
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spelling pubmed-90242212022-04-23 The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway Yang, Xiaoli Ali, Shafaqat Zhao, Manman Richter, Lisa Schäfer, Vanessa Schliehe-Diecks, Julian Frank, Marian Qi, Jing Larsen, Pia-Katharina Skerra, Jennifer Islam, Heba Wachtmeister, Thorsten Alter, Christina Huang, Anfei Bhatia, Sanil Köhrer, Karl Kirschning, Carsten Weighardt, Heike Kalinke, Ulrich Kalscheuer, Rainer Uhrberg, Markus Scheu, Stefanie Front Immunol Immunology Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte–macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFNβ production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-κB activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies. Frontiers Media S.A. 2022-04-08 /pmc/articles/PMC9024221/ /pubmed/35464417 http://dx.doi.org/10.3389/fimmu.2022.856230 Text en Copyright © 2022 Yang, Ali, Zhao, Richter, Schäfer, Schliehe-Diecks, Frank, Qi, Larsen, Skerra, Islam, Wachtmeister, Alter, Huang, Bhatia, Köhrer, Kirschning, Weighardt, Kalinke, Kalscheuer, Uhrberg and Scheu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yang, Xiaoli
Ali, Shafaqat
Zhao, Manman
Richter, Lisa
Schäfer, Vanessa
Schliehe-Diecks, Julian
Frank, Marian
Qi, Jing
Larsen, Pia-Katharina
Skerra, Jennifer
Islam, Heba
Wachtmeister, Thorsten
Alter, Christina
Huang, Anfei
Bhatia, Sanil
Köhrer, Karl
Kirschning, Carsten
Weighardt, Heike
Kalinke, Ulrich
Kalscheuer, Rainer
Uhrberg, Markus
Scheu, Stefanie
The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
title The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
title_full The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
title_fullStr The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
title_full_unstemmed The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
title_short The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway
title_sort mycotoxin beauvericin exhibits immunostimulatory effects on dendritic cells via activating the tlr4 signaling pathway
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024221/
https://www.ncbi.nlm.nih.gov/pubmed/35464417
http://dx.doi.org/10.3389/fimmu.2022.856230
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