Release of High Mobility Group Box 1 by Dendritic Cells Controls T Cell Activation via the Receptor for Advanced Glycation End Products

Dumitriu, Ingrid E.; Baruah, Paramita; Valentinis, Barbara; Voll, Reinhard; Herrmann, Martin; Nawroth, Peter P.; Arnold, Bernd; Bianchi, Marco E.; Manfredi, Angelo A.; Rovere‐Querini, Patrizia

doi:10.4049/jimmunol.174.12.7506

Cited by 465 publications

(399 citation statements)

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“…Endogenous or exogenous HMGB1 is known to play a role in DC activation and CD4 1 T-cell polarization [20] and also behaves as a potent inflammatory mediator in autoimmune disease, cancer, and ischemia/ reperfusion (I/R) injury [30]. It was well known that T-cell activation required both T-cell antigen receptor stimulation (signal 1) and additional costimulatory signals (signal 2).…”

Section: Discussionmentioning

confidence: 99%

“…As an important inflammatory factor, HMGB1 is involved in many cardiovascular diseases, autoimmune disease pathogenesis, and CD4 1 T-cell differentiation and modulation [20,30]. Therefore, in the present study, we aimed to clarify (i) whether HMGB1 contributes to the progression of EAM and (ii) whether HMGB1 expression is associated with Th17-cell activity in EAM.…”

Section: Introductionmentioning

confidence: 94%

“…Some autoimmune responses formerly attributed to Th1 cells, such as experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and inflammatory bowel disease (IBD), may actually to be mediated, at least in part, by Th17 cells [25,26]. There is also evidence that Th17 cells may contribute to autoimmune myocarditis development [27][28][29].As an important inflammatory factor, HMGB1 is involved in many cardiovascular diseases, autoimmune disease pathogenesis, and CD4 1 T-cell differentiation and modulation [20,30]. Therefore, in the present study, we aimed to clarify (i) whether HMGB1 contributes to the progression of EAM and (ii) whether HMGB1 expression is associated with Th17-cell activity in EAM.…”

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confidence: 99%

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HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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High-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been implicated in cardiovascular diseases. Dilated cardiomyopathy (DCM), one of the leading causes of heart failure, is often caused by coxsackievirus B3-triggered myocarditis and promoted by the post-infectious autoimmune process. Th17 cells, a novel CD4 1 T subset, may be important in the pathogenesis of autoimmune myocarditis. In the present study, we attempted to block HMGB1 function with a monoclonal antibody specific for HMGB1 B box and investigated the effects of the blockade on Th17 cells and experimental autoimmune myocarditis (EAM). After induction of EAM, HMGB1 protein levels were significantly elevated both in the heart and blood. Administration of an anti-HMGB1 B box mAb attenuated cardiac pathological changes and reduced the number of infiltrating inflammatory cells in the heart during EAM. These protective effects of HMGB1 blockade correlated with a reduced number of Th17 cells in local tissues and lower levels of IL-17 in the serum. Furthermore, in vitro, studies demonstrated that HMGB1 promoted Th17-cell expansion. Therefore, we speculate that HMGB1 blockade ameliorates cardiac pathological changes in EAM by suppressing Th17 cells.Key words: Dilated cardiomyopathy . Experimental myocarditis . HMGB1 . Th17 cells IntroductionHigh-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been functionally characterized as an alarmin or damage-associated molecular pattern (DAMP) [1,2]. It is constitutively expressed in quiescent cells and stored in the nucleus [3]. HMGB1 is one of the most evolutionarily conserved proteins in eukaryotes, with 100% identity between mice and rats, and 99% identity between rodents and humans [3].HMGB1 has been shown to be involved in both infectious and non-infectious inflammatory disease [2,4]. HMGB1 is released into the extracellular milieu during cell apoptosis/death [5], and by macrophages and monocytes in response to cellular stress or injury [6]. HMGB1 binds to the endogenous receptor for advanced glycation endproducts [7], exogenous toll-like receptor 2/4/9 (TLR2/4/9) [8,9], and CD24/Siglec-10 [10], and induces the expression of proinammatory cytokines, chemokines, and adhesion molecules [3,6]. Although, HMGB1 was initially 3586thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].Dilated cardiomyopathy (DCM) is one of the leading causes of severe heart failure and the most common indication for heart transplantation. DCM is often caused by coxsackievirus B3-triggered myocarditis [21]. Experimental autoimmune myocarditis (EAM) is a mouse model of postinfectious myocarditis, characterized by inflammatory infiltration of the myocardium and cardiac myocyte ne...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

mentioning

confidence: 99%

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HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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“…RAGE (Official symbol: AGER (advanced glycosylation end productspecific receptor) binds HMGB1 and S100 proteins and has been reported to mediate the adjuvant 87 or inflammatory effects 51 of these DAMPs. A number of molecules including CD91 88 , CD14 48 and scavenger receptors 89 have been implicated in the action of HSPs.…”

Section: Receptors For Dampsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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“…Other studies, however, indicate a direct effect of RAGE on mobilisation of dendritic cells [79] and T cell migration, localisation, activation and differentiation [35,75,80], whereas HMGB1 signalling through RAGE seems to be required for clonal expansion, survival and functional polarisation of naive T cells [81]. Furthermore, clonal populations of Rage −/− mice-derived T cells adoptively Monocytes and macrophages seem to be central to the initiation and propagation of RAGE-dependent inflammation transferred into wild-type recipients showed reduced responses [82].…”

Section: The Role Of Rage In Various Pathological Settingsmentioning

confidence: 99%

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

2009

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The pattern recognition receptor or receptor for AGE (RAGE) is constitutionally expressed in a few cell types only. However in almost all cells studied so far it is induced by reactions known to initiate inflammation. Its biological activity seems to be mainly dependent on the presence of its various ligands, including AGE, S100-calcium binding protein/calgranulins, high-mobility group protein 1, amyloid-β-peptides and the family of β-sheet fibrils, all known to be elevated in chronic metabolic, malignant and inflammatory diseases. The RAGE pathway interacts with cytokine-, lipopolysaccharide-, oxidised LDL-and glucose-triggered cellular reactions by turning a short-lasting inflammatory response into a sustained change of cellular function driven by perpetuated activation of the proinflammatory transcription factor, nuclear factor kappa-B. RAGE-mediated persistent cell activation is of pivotal importance in various experimental and clinical settings, including diabetes and its complications, neurodegeneration, ageing, tumour growth, and autoimmune and infectious inflammatory disease. Due to RAGE's central role in maintaining perpetuated cell activation, various therapeutic attempts to block RAGE or its ligands are currently under investigation. Despite broad experimental evidence for the role of RAGE in chronic disease, knowledge of its physiological function is still missing, limiting predictions about safety of long-term inhibition of RAGE×ligand interaction in chronic diseases.

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Release of High Mobility Group Box 1 by Dendritic Cells Controls T Cell Activation via the Receptor for Advanced Glycation End Products

Cited by 465 publications

References 43 publications

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

How dying cells alert the immune system to danger

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

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