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

doi:10.1186/1479-5876-12-211

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 journal › Article › peer-review

75 Scopus citations

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 language	English (US)
Article number	211
Journal	Journal of translational medicine
Volume	12
Issue number	1
DOIs	https://doi.org/10.1186/1479-5876-12-211
State	Published - Aug 14 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1186/1479-5876-12-211

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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), Article 211. https://doi.org/10.1186/1479-5876-12-211

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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",

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doi = "10.1186/1479-5876-12-211",

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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.

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

Abstract

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