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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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.856230/full |
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| author | Xiaoli Yang Shafaqat Ali Manman Zhao Lisa Richter Vanessa Schäfer Julian Schliehe-Diecks Marian Frank Jing Qi Pia-Katharina Larsen Jennifer Skerra Heba Islam Thorsten Wachtmeister Christina Alter Anfei Huang Sanil Bhatia Karl Köhrer Carsten Kirschning Heike Weighardt Ulrich Kalinke Ulrich Kalinke Rainer Kalscheuer Markus Uhrberg Stefanie Scheu |
| author_facet | Xiaoli Yang Shafaqat Ali Manman Zhao Lisa Richter Vanessa Schäfer Julian Schliehe-Diecks Marian Frank Jing Qi Pia-Katharina Larsen Jennifer Skerra Heba Islam Thorsten Wachtmeister Christina Alter Anfei Huang Sanil Bhatia Karl Köhrer Carsten Kirschning Heike Weighardt Ulrich Kalinke Ulrich Kalinke Rainer Kalscheuer Markus Uhrberg Stefanie Scheu |
| author_sort | Xiaoli Yang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T05:53:06Z |
| format | Article |
| id | doaj.art-e7db736d19e84cc1b3620305b013c974 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T05:53:06Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e7db736d19e84cc1b3620305b013c9742022-12-21T23:14:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-04-011310.3389/fimmu.2022.856230856230The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling PathwayXiaoli Yang0Shafaqat Ali1Manman Zhao2Lisa Richter3Vanessa Schäfer4Julian Schliehe-Diecks5Marian Frank6Jing Qi7Pia-Katharina Larsen8Jennifer Skerra9Heba Islam10Thorsten Wachtmeister11Christina Alter12Anfei Huang13Sanil Bhatia14Karl Köhrer15Carsten Kirschning16Heike Weighardt17Ulrich Kalinke18Ulrich Kalinke19Rainer Kalscheuer20Markus Uhrberg21Stefanie Scheu22Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, ChinaInstitute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyDepartment of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, GermanyInstitute of Medical Microbiology, University Hospital of Essen, University of Duisburg-Essen, Essen, GermanyBiological and Medical Research Center (BMFZ), Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Molecular Cardiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany0Institute for Systems Immunology, Julius-Maximilians-Universität of Würzburg (JMU), Würzburg, GermanyDepartment of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, GermanyBiological and Medical Research Center (BMFZ), Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Medical Microbiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany1Immunology and Environment, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany2Cluster of Excellence - Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Hannover, GermanyInstitute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyInstitute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, GermanyInstitute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyBeauvericin (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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.856230/fullbeauvericinImmunostimulatory activitiesdendritic cellsactivateTLR4 (Toll-like receptor 4) |
| spellingShingle | Xiaoli Yang Shafaqat Ali Manman Zhao Lisa Richter Vanessa Schäfer Julian Schliehe-Diecks Marian Frank Jing Qi Pia-Katharina Larsen Jennifer Skerra Heba Islam Thorsten Wachtmeister Christina Alter Anfei Huang Sanil Bhatia Karl Köhrer Carsten Kirschning Heike Weighardt Ulrich Kalinke Ulrich Kalinke Rainer Kalscheuer Markus Uhrberg Stefanie Scheu The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway Frontiers in Immunology beauvericin Immunostimulatory activities dendritic cells activate TLR4 (Toll-like receptor 4) |
| 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 | beauvericin Immunostimulatory activities dendritic cells activate TLR4 (Toll-like receptor 4) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.856230/full |
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