PT  - JOURNAL ARTICLE
AU  - Xiaoli Yang
AU  - Shafaqat Ali
AU  - Manman Zhao
AU  - Lisa Richter
AU  - Vanessa Schäfer
AU  - Julian Schliehe-Diecks
AU  - Marian Frank
AU  - Jing Qi
AU  - Pia-Katharina Larsen
AU  - Jennifer Skerra
AU  - Heba Islam
AU  - Thorsten Wachtmeister
AU  - Christina Alter
AU  - Anfei Huang
AU  - Sanil Bhatia
AU  - Karl Köhrer
AU  - Carsten Kirschning
AU  - Heike Weighardt
AU  - Ulrich Kalinke
AU  - Rainer Kalscheuer
AU  - Markus Uhrberg
AU  - Stefanie Scheu
TI  - The mycotoxin Beauvericin exhibits immunostimulatory effects on dendritic cells via activating the TLR4 signaling pathway
AID  - 10.1101/2022.01.20.476919
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.20.476919
4099  - http://biorxiv.org/content/early/2022/01/26/2022.01.20.476919.short
4100  - http://biorxiv.org/content/early/2022/01/26/2022.01.20.476919.full
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.