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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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
Externally publishedYes

Fingerprint

HMGB1 Protein
Dendritic Cells
Chemical activation
Peptides
Interleukin-6
Dynamins
Clathrin
Subunit Vaccines
Macrophages
p38 Mitogen-Activated Protein Kinases
Endocytosis
Interferons
Amplification
Vaccines
Molecules

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Saenz, R., Futalan, D., Leutenez, L., Eekhout, F., Fecteau, J. F., Sundelius, S., ... 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

TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant. / Saenz, Rebecca; Futalan, Diahnn; Leutenez, Lien; Eekhout, Fien; Fecteau, Jessie F.; Sundelius, Simeon; Sundqvist, Stig; Larsson, Marie; Hayashi, Tomoko; Minev, Boris; Carson, Dennis; Esener, Sadik; Messmer, Bradley; Messmer, Davorka.

In: Journal of Translational Medicine, Vol. 12, No. 1, 211, 14.08.2014.

Research output: Contribution to journalArticle

Saenz, R, Futalan, D, Leutenez, L, Eekhout, F, Fecteau, JF, 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, vol. 12, no. 1, 211. https://doi.org/10.1186/1479-5876-12-211
Saenz, Rebecca ; Futalan, Diahnn ; Leutenez, Lien ; Eekhout, Fien ; Fecteau, Jessie F. ; Sundelius, Simeon ; Sundqvist, Stig ; Larsson, Marie ; Hayashi, Tomoko ; Minev, Boris ; Carson, Dennis ; Esener, Sadik ; Messmer, Bradley ; Messmer, Davorka. / TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant. In: Journal of Translational Medicine. 2014 ; Vol. 12, No. 1.
@article{45eccaa69a9f49d4851d5510aecce97b,
title = "TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant",
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.",
author = "Rebecca Saenz and Diahnn Futalan and Lien Leutenez and Fien Eekhout and Fecteau, {Jessie F.} and Simeon Sundelius and Stig Sundqvist and Marie Larsson and Tomoko Hayashi and Boris Minev and Dennis Carson and Sadik Esener and Bradley Messmer and Davorka Messmer",
year = "2014",
month = "8",
day = "14",
doi = "10.1186/1479-5876-12-211",
language = "English (US)",
volume = "12",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant

AU - Saenz, Rebecca

AU - Futalan, Diahnn

AU - Leutenez, Lien

AU - Eekhout, Fien

AU - Fecteau, Jessie F.

AU - Sundelius, Simeon

AU - Sundqvist, Stig

AU - Larsson, Marie

AU - Hayashi, Tomoko

AU - Minev, Boris

AU - Carson, Dennis

AU - Esener, Sadik

AU - Messmer, Bradley

AU - Messmer, Davorka

PY - 2014/8/14

Y1 - 2014/8/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906829514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906829514&partnerID=8YFLogxK

U2 - 10.1186/1479-5876-12-211

DO - 10.1186/1479-5876-12-211

M3 - Article

VL - 12

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

IS - 1

M1 - 211

ER -