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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2014

Open Access 01-12-2014 | Research

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

Authors: 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

Published in: Journal of Translational Medicine | Issue 1/2014

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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.
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Literature
1.
2.
Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature. 1998, 392: 245-252.CrossRefPubMed
3.
Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007, 81: 1-5.CrossRefPubMed
4.
5.
Gallucci S, Matzinger P: Danger signals: SOS to the immune system. Curr Opin Immunol. 2001, 13: 114-119.CrossRefPubMed
6.
Gallucci S, Lolkema M, Matzinger P: Natural adjuvants: endogenous activators of dendritic cells. Nat Med. 1999, 5: 1249-1255.CrossRefPubMed
7.
Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N: Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J Exp Med. 2000, 191: 423-434.PubMedCentralCrossRefPubMed
8.
Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK: Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol. 2000, 12: 1539-1546.CrossRefPubMed
9.
10.
Bustin M, Lehn DA, Landsman D: Structural features of the HMG chromosomal proteins and their genes. Biochimica Et Biophysica Acta. 1990, 1049: 231-243.CrossRefPubMed
11.
Bustin M, Reeves R: High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog Nucleic Acid Res Mol Biol. 1996, 54: 35-100.CrossRefPubMed
12.
Wang H, Vishnubhakat JM, Bloom O, Zhang M, Ombrellino M, Sama A, Tracey KJ: Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery. 1999, 126: 389-392.CrossRefPubMed
13.
Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson_Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ: High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. The Journal of Experimental Medicine. 2000, 192: 565-570.PubMedCentralCrossRefPubMed
14.
Hreggvidsdottir HS, Ostberg T, Wahamaa H, Schierbeck H, Aveberger AC, Klevenvall L, Palmblad K, Ottosson L, Andersson U, Harris HE: The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation. J Leukoc Biol. 2009, 86: 655-662.CrossRefPubMed
15.
Scaffidi P, Misteli T, Bianchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002, 418: 191-195.CrossRefPubMed
16.
Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, Dumitriu IE, Muller S, Iannacone M, Traversari C, Bianchi ME, Manfredi A: HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 2004, 5: 825-830.PubMedCentralCrossRefPubMed
17.
Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D, Morser J, Stern D, Schmidt AM: The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995, 270: 25752-25761.CrossRefPubMed
18.
Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P: Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol. 2005, 35: 2184-2190.CrossRefPubMed
19.
Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E: Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2004, 279: 7370-7377.CrossRefPubMed
20.
van Zoelen MA, Yang H, Florquin S, Meijers JC, Akira S, Arnold B, Nawroth PP, Bierhaus A, Tracey KJ, van der Poll T: Role of Toll-Like Receptors 2 and 4, and the Receptor for Advanced Glycation End Products (Rage) in Hmgb1 Induced Inflammation in Vivo. Shock. 2009, 31 (3): 280-284.PubMedCentralCrossRefPubMed
21.
Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, Fenton MJ, Tracey KJ, Yang H: HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock. 2006, 26: 174-179.CrossRefPubMed
22.
Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E: High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol. 2006, 290: C917-C924.CrossRefPubMed
23.
Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J, Lu B, Chavan S, Rosas-Ballina M, Al-Abed Y, Akira S, Bierhaus A, Erlandsson-Harris H, Andersson U, Tracey KJ: A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A. 2010, 107: 11942-11947.PubMedCentralCrossRefPubMed
24.
Ivanov S, Dragoi AM, Wang X, Dallacosta C, Louten J, Musco G, Sitia G, Yap GS, Wan Y, Biron CA, Bianchi ME, Wang H, Chu WM: A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood. 2007, 110: 1970-1981.PubMedCentralCrossRefPubMed
25.
Orlova VV, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, Ballantyne CM, Gahmberg CG, Bianchi ME, Nawroth PP, Chavakis T: A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J. 2007, 26: 1129-1139.PubMedCentralCrossRefPubMed
26.
Rauvala H, Rouhiainen A: Physiological and pathophysiological outcomes of the interactions of HMGB1 with cell surface receptors. Biochim Biophys Acta. 2010, 1799: 164-170.CrossRefPubMed
27.
Salmivirta M, Rauvala H, Elenius K, Jalkanen M: Neurite growth-promoting protein (amphoterin, p30) binds syndecan. Exp Cell Res. 1992, 200: 444-451.CrossRefPubMed
28.
Milev P, Chiba A, Haring M, Rauvala H, Schachner M, Ranscht B, Margolis RK, Margolis RU: High affinity binding and overlapping localization of neurocan and phosphacan/protein-tyrosine phosphatase-zeta/beta with tenascin-R, amphoterin, and the heparin-binding growth-associated molecule. J Biol Chem. 1998, 273: 6998-7005.CrossRefPubMed
29.
30.
Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X, Harris HE, Czura CJ, Wang H, Ulloa L, Wang H, Warren HS, Moldawer LL, Fink MP, Andersson U, Tracey KJ, Yang H: Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med. 2003, 9: 37-45.PubMedCentralPubMed
31.
Yang H, Wang H, Czura CJ, Tracey KJ: HMGB1 as a cytokine and therapeutic target. J Endotoxin Res. 2002, 8: 469-472.CrossRefPubMed
32.
Telusma G, Datta S, Mihajlov I, Ma W, Li J, Yang H, Newman W, Messmer BT, Minev B, Schmidt-Wolf IG, Tracey KJ, Chiorazzi N, Messmer D: Dendritic cell activating peptides induce distinct cytokine profiles. Int Immunol. 2006, 18: 1563-1573.CrossRefPubMed
33.
Saenz R, Souza Cda S, Huang CT, Larsson M, Esener S, Messmer D: HMGB1-derived peptide acts as adjuvant inducing immune responses to peptide and protein antigen. Vaccine. 2010, 28: 7556-7562.PubMedCentralCrossRefPubMed
34.
Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman RM: Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992, 176: 1693-1702.CrossRefPubMed
35.
Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R: TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol. 2008, 9: 361-368.PubMedCentralCrossRefPubMed
36.
Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T: Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell. 2006, 10: 839-850.CrossRefPubMed
37.
Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, Tracey KJ, Chiorazzi N: High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol. 2004, 173: 307-313.CrossRefPubMed
38.
Huttunen HJ, Kuja-Panula J, Rauvala H: Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J Biol Chem. 2002, 277: 38635-38646.CrossRefPubMed
39.
Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, Choe KH, Strassheim D, Pitts TM, Tracey KJ, Abraham E: Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol. 2003, 284: C870-C879.CrossRefPubMed
40.
Caskey M, Lefebvre F, Filali-Mouhim A, Cameron MJ, Goulet JP, Haddad EK, Breton G, Trumpfheller C, Pollak S, Shimeliovich I, Duque-Alarcon A, Pan L, Nelkenbaum A, Salazar AM, Schlesinger SJ, Steinman RM, Sekaly RP: Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J Exp Med. 2011, 208: 2357-2366.PubMedCentralCrossRefPubMed
Metadata
Title
TLR4-dependent activation of dendritic cells by an HMGB1-derived peptide adjuvant
Authors
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
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2014
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-12-211

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