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

Abstract

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.

The functional role of L-fucose on dendritic cell function and polarization

“…However, given that the observed increases in DC abundance intratumorally and from BM-derived DCs are comparable, we are confident that the findings from bmDCs would translate to intratumor DCs. Additionally, bmDCs have previously been used to deduce specific aspects of DC biology using similar culturing conditions to that of this study (109)(110)(111)(112)(113), further supporting the validity of this methodology. Interestingly, through our in vivo and ex vivo studies we observed that L-fuc increases cDC1 and moDC abundance in similar proportions.…”

The Contribution of Antimicrobial Peptides to Immune Cell Function: A Review of Recent Advances

“…Pep19-2.5 is a synthetic anti-lipopolysaccharide peptide. In LPS-stimulated human monocyte-derived DCs and Langerhans-like cells, Pep19-2.5 blocks IL-6 secretion, downregulates expression of maturation markers and inhibits DC migration [ 183 ].…”

Beauvericin suppresses the proliferation and pulmonary metastasis of osteosarcoma by selectively inhibiting TGFBR2 pathway

“…Beauvericin (BEA), a cyclic hexadepsipeptide, is one of the active ingredients of the traditional Chinese medicine Bombyx batryticatus . Accumulating studies have shown that BEA exerts a broad spectrum of biological effects, such as antimicrobial and anti-inflammatory effects 24 , and has an immunostimulatory effect on dendritic cells 25 . Studies have also revealed that BEA shows extensive anticancer effects and inhibits the progression of many types of cancer, such as colorectal cancer 26 , pancreatic cancer 27 , and non-small cell lung cancer 28 .…”