RT Journal Article SR Electronic T1 The mycotoxin Beauvericin exhibits immunostimulatory effects on dendritic cells via activating the TLR4 signaling pathway JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.20.476919 DO 10.1101/2022.01.20.476919 A1 Xiaoli Yang A1 Shafaqat Ali A1 Manman Zhao A1 Lisa Richter A1 Vanessa Schäfer A1 Julian Schliehe-Diecks A1 Marian Frank A1 Jing Qi A1 Pia-Katharina Larsen A1 Jennifer Skerra A1 Heba Islam A1 Thorsten Wachtmeister A1 Christina Alter A1 Anfei Huang A1 Sanil Bhatia A1 Karl Köhrer A1 Carsten Kirschning A1 Heike Weighardt A1 Ulrich Kalinke A1 Rainer Kalscheuer A1 Markus Uhrberg A1 Stefanie Scheu YR 2022 UL http://biorxiv.org/content/early/2022/01/26/2022.01.20.476919.abstract 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 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.Competing Interest StatementThe authors have declared no competing interest.