PMID- 35464417 OWN - NLM STAT- MEDLINE DCOM- 20220426 LR - 20220716 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - The Mycotoxin Beauvericin Exhibits Immunostimulatory Effects on Dendritic Cells via Activating the TLR4 Signaling Pathway. PG - 856230 LID - 10.3389/fimmu.2022.856230 [doi] LID - 856230 AB - 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 IFNbeta 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-kappaB 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. CI - Copyright (c) 2022 Yang, Ali, Zhao, Richter, Schafer, Schliehe-Diecks, Frank, Qi, Larsen, Skerra, Islam, Wachtmeister, Alter, Huang, Bhatia, Kohrer, Kirschning, Weighardt, Kalinke, Kalscheuer, Uhrberg and Scheu. FAU - Yang, Xiaoli AU - Yang X AD - Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Ali, Shafaqat AU - Ali S AD - Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Zhao, Manman AU - Zhao M AD - Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. FAU - Richter, Lisa AU - Richter L AD - Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Schafer, Vanessa AU - Schafer V AD - Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Schliehe-Diecks, Julian AU - Schliehe-Diecks J AD - Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany. FAU - Frank, Marian AU - Frank M AD - Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Qi, Jing AU - Qi J AD - Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany. FAU - Larsen, Pia-Katharina AU - Larsen PK AD - Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany. FAU - Skerra, Jennifer AU - Skerra J AD - Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany. FAU - Islam, Heba AU - Islam H AD - Institute of Medical Microbiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. FAU - Wachtmeister, Thorsten AU - Wachtmeister T AD - Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Alter, Christina AU - Alter C AD - Institute of Molecular Cardiology, Medical Faculty, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Huang, Anfei AU - Huang A AD - Institute for Systems Immunology, Julius-Maximilians-Universitat of Wurzburg (JMU), Wurzburg, Germany. FAU - Bhatia, Sanil AU - Bhatia S AD - Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany. FAU - Kohrer, Karl AU - Kohrer K AD - Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Kirschning, Carsten AU - Kirschning C AD - Institute of Medical Microbiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. FAU - Weighardt, Heike AU - Weighardt H AD - Immunology and Environment, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany. FAU - Kalinke, Ulrich AU - Kalinke U AD - Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany. AD - Cluster of Excellence - Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Hannover, Germany. FAU - Kalscheuer, Rainer AU - Kalscheuer R AD - Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Uhrberg, Markus AU - Uhrberg M AD - Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany. FAU - Scheu, Stefanie AU - Scheu S AD - Institute of Medical Microbiology and Hospital Hygiene, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220408 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Cytokines) RN - 0 (Depsipeptides) RN - 0 (Mycotoxins) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (TLR4 protein, human) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 187348-17-0 (Interleukin-12) RN - 26S048LS2R (beauvericin) SB - IM MH - Adaptor Proteins, Vesicular Transport/metabolism MH - Animals MH - Cytokines/metabolism MH - Dendritic Cells MH - Depsipeptides MH - HEK293 Cells MH - Humans MH - Interleukin-12/metabolism MH - Mice MH - *Mycotoxins MH - Myeloid Differentiation Factor 88/genetics/metabolism MH - Signal Transduction MH - *Toll-Like Receptor 4/metabolism PMC - PMC9024221 OTO - NOTNLM OT - Immunostimulatory activities OT - TLR4 (Toll-like receptor 4) OT - activate OT - beauvericin OT - dendritic cells COIS- Authors P-KL, UK, and JS are employed by Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/04/26 06:00 MHDA- 2022/04/27 06:00 PMCR- 2022/01/01 CRDT- 2022/04/25 05:33 PHST- 2022/01/16 00:00 [received] PHST- 2022/03/18 00:00 [accepted] PHST- 2022/04/25 05:33 [entrez] PHST- 2022/04/26 06:00 [pubmed] PHST- 2022/04/27 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.856230 [doi] PST - epublish SO - Front Immunol. 2022 Apr 8;13:856230. doi: 10.3389/fimmu.2022.856230. eCollection 2022.