TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant

Rebecca Saenz, Diahnn Futalan, Lien Leutenez, Fien Eekhout, Jessie F. Fecteau, Simeon Sundelius, Stig Sundqvist, Marie Larsson, Tomoko Hayashi, Boris Minev, Dennis Carson, Sadik Esener, Bradley Messmer, Davorka Messmer

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Abstract

High mobility group box protein 1 (HMGB1) acts as an endogenous danger molecule that is released from necrotic cells and activated macrophages. We have previously shown that peptide Hp91, whose sequence corresponds to an area within the B-Box domain of HMGB1, activates dendritic cells (DCs) and acts as an adjuvant in vivo. Here we investigated the underlying mechanisms of Hp91-mediated DC activation. Hp91-induced secretion of IL-6 was dependent on clathrin- and dynamin-driven endocytosis of Hp91 and mediated through a MyD88- and TLR4-dependent pathway involving p38 MAPK and NFκB. Endosomal TLR4 has been shown to activate the MyD88-independent interferon pathway. Hp91-induced activation of pIRF3 and IL-6 secretion was reduced in IFNαβR knockout DCs, suggesting an amplification loop via the IFNαβR. These findings elucidate the mechanisms by which Hp91 acts as immunostimulatory peptide and may serve as a guide for the future development of synthetic Th1-type peptide adjuvants for vaccines.

Original languageEnglish (US)
Article number211
JournalJournal of translational medicine
Volume12
Issue number1
DOIs
StatePublished - Aug 14 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Saenz, R., Futalan, D., Leutenez, L., Eekhout, F., Fecteau, J. F., Sundelius, S., Sundqvist, S., Larsson, M., Hayashi, T., Minev, B., Carson, D., Esener, S., Messmer, B., & Messmer, D. (2014). TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant. Journal of translational medicine, 12(1), [211]. https://doi.org/10.1186/1479-5876-12-211