The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation

Hreggvidsdottir, Hulda S.; Östberg, Therese; Wähämaa, Heidi; Schierbeck, Hanna; Aveberger, Ann-Charlotte; Klevenvall, Lena; Palmblad, Karin; Ottosson, Lars; Andersson, Ulf; Harris, Helena Erlandsson

doi:10.1189/jlb.0908548

Cited by 271 publications

(262 citation statements)

References 33 publications

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“…Since the original description of HMGB1 activity in stimulating macrophage cytokine release (23), investigations have revealed that HMGB1 can act in synergy with other inflammatory mediators to promote cytokine stimulation (24). Therefore, there has been an ongoing debate concerning whether HMGB1 per se, uncomplexed to partner molecules, is capable of inducing cytokine production to promote inflammation.…”

Section: Discussionmentioning

confidence: 99%

Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)

Yang

Lundbäck

Ottosson

et al. 2011

Mol Med

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377

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High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is released passively during cell injury and necrosis, and secreted actively by immune cells. HMGB1 contains three conserved redox-sensitive cysteine residues: C23 and C45 can form an intramolecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. Using tandem mass spectrometric analysis, we now have established that the C106 thiol and the C23-C45 disulfide bond are required for HMGB1 to induce nuclear NF-κB translocation and tumor necrosis factor (TNF) production in macrophages. Both irreversible oxidation to sulphonates and complete reduction to thiols of these cysteines inhibited TNF production markedly. In a proof of concept murine model of hepatic necrosis induced by acetaminophen, during inflammation, the predominant form of serum HMGB1 is the active one, containing a C106 thiol group and a disulfide bond between C23 and C45, whereas the inactive form of HMGB1, containing terminally oxidized cysteines, accumulates during inflammation resolution and hepatic regeneration. These results reveal critical posttranslational redox mechanisms that control the proinflammatory activity of HMGB1 and its inactivation during pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)

Yang

Lundbäck

Ottosson

et al. 2011

Mol Med

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377

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“…HMGB1, as an extracellular mediator of inammation [43][44][45], occurs as a consequence of either passive release from necrotic cells [6] or active secretion by lymphocytes, involving extensive acetylation and transfer to secretory lysosomes [46,47]. 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].…”

Section: Discussionmentioning

confidence: 99%

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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“…This leads to the activation of innate and adaptive immunity, cytokine, chemokine, and metalloprotease release and ensued pro-migration and pro-inflammatory outcomes (Andersson et al 2000, Scaffidi et al 2002, Rouhiainen et al 2004, Andersson & Tracey 2011. Of interest, HMGB1 has also been shown to form complexes with many pro-inflammatory mediators and enhance their respective actions in a synergistic manner (Hreggvidsdottir et al 2009). Furthermore, HMGB1 levels are elevated in multiple animal models of sterile injurious events (Tsung et al 2014) and in humans with acute organ injury, autoimmune diseases or cancer (Tong et al 2011.…”

Section: Hmgb1mentioning

confidence: 99%

Sterile inflammation and pregnancy complications: a review

Nadeau-Vallée¹,

Obari²,

Palacios³

et al. 2016

Reproduction

219

161

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Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on their mechanism of action. In this review, we discuss the role of sterile inflammation in reproduction, including early implantation and pregnancy complications. Particularly, we focus on major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA (especially that of fetal origin) while giving an overview of the potential role of other candidate alarmins.Reproduction (2016) 152 R277-R292

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The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation

Cited by 271 publications

References 33 publications

Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)

Redox Modification of Cysteine Residues Regulates the Cytokine Activity of High Mobility Group Box-1 (HMGB1)

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

Sterile inflammation and pregnancy complications: a review

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