Regulation of Posttranslational Modifications of HMGB1 During Immune Responses

Tang, Yiting; Zhao, Xin; Antoine, Daniel J.; Xiao, Xianzhong; Wang, Haichao; Andersson, Ulf; Billiar, Timothy R.; Tracey, Kevin J.; Lü, Ben

doi:10.1089/ars.2015.6409

Cited by 109 publications

(94 citation statements)

References 102 publications

(205 reference statements)

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“…The protein harbors 3 conserved cysteine residues at position 23, 45, and 106, and the redox state of these cysteines determine whether HMGB1 functions as a chemokine or as a proinflammatory cytokine (11–14). HMGB1, actively secreted by activated immune cells or passively released from dying cells, is a mixture of redox isoforms with distinct posttranslational modifications (5, 15, 16). Administration of anti-HMGB1 antibodies confers significant protection in animal models of experimental sepsis, endotoxemia, ischemia reperfusion injury, trauma, hepatitis, and other syndromes (3–5, 17).…”

Section: Introductionmentioning

confidence: 99%

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Yang¹,

Wang²,

Levine³

et al. 2016

JCI Insight

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103

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Secreted by activated cells or passively released by damaged cells, extracellular HMGB1 is a prototypical damage-associated molecular pattern (DAMP) inflammatory mediator. During the course of developing extracorporeal approaches to treating injury and infection, we inadvertently discovered that haptoglobin, the acute phase protein that binds extracellular hemoglobin and targets cellular uptake through CD163, also binds HMGB1. Haptoglobin-HMGB1 complexes elicit the production of antiinflammatory enzymes (heme oxygenase-1) and cytokines (e.g., IL-10) in WT but not in CD163-deficient macrophages. Genetic disruption of haptoglobin or CD163 expression significantly enhances mortality rates in standardized models of intra-abdominal sepsis in mice. Administration of haptoglobin to WT and to haptoglobin gene-deficient animals confers significant protection. These findings reveal a mechanism for haptoglobin modulation of the inflammatory action of HMGB1, with significant implications for developing experimental strategies targeting HMGB1-dependent inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Yang¹,

Wang²,

Levine³

et al. 2016

JCI Insight

Self Cite

103

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“…It is becoming increasingly clear that different types of stressors and cell death modes release different redox isoforms of HMGB1 into the extracellular environment [27]. Recently, it has been shown that post-translational oxidative modifications of the three cysteine residues present in HMGB1 generate different redox isoforms that have the ability to interact with multiple diverse receptors, mediating separate inflammatory functions.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. Methods: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. Results and Conclusions: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.

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“…The disulfide linkage of C23 and C45 is required for the cytokine-stimulating activity of HMGB1 and C106 must remain in its reduced form as a thiol at the same time [23]. In addition, both the acetylation of HMGB1 within its nuclear localization sequences [24] and the methylation at lysine 42 [25] promote HMGB1 release by mobilizing HMGB1 from the nucleus to the cytoplasm.…”

Section: Hmgb1mentioning

confidence: 99%

The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes

Wang

Zhong

Zhang

et al. 2016

Journal of Diabetes Research

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Significance. With an alarming increase in recent years, diabetes mellitus has become a global challenge. Despite advances in treatment of diabetes mellitus, currently, medications available are unable to control the progression of diabetes and its complications. Growing evidence suggests that inflammation is an important pathogenic mediator in the development of diabetes mellitus. The perspectives including suggestions for new therapies involving the shift from metabolic stress to inflammation should be taken into account. Critical Issues. High-mobility group box 1 (HMGB1), a nonhistone nuclear protein regulating gene expression, was rediscovered as an endogenous danger signal molecule to trigger inflammatory responses when released into extracellular milieu in the late 1990s. Given the similarities of inflammatory response in the development of T2D, we will discuss the potential implication of HMGB1 in the pathogenesis of T2D. Importantly, we will summarize and renovate the role of HMGB1 and HMGB1-mediated inflammatory pathways in adipose tissue inflammation, insulin resistance, and islet dysfunction. Future Directions. HMGB1 and its downstream receptors RAGE and TLRs may serve as potential antidiabetic targets. Current and forthcoming projects in this territory will pave the way for prospective approaches targeting the center of HMGB1-mediated inflammation to improve T2D and its complications.

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Regulation of Posttranslational Modifications of HMGB1 During Immune Responses

Cited by 109 publications

References 102 publications

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Identification of CD163 as an antiinflammatory receptor for HMGB1-haptoglobin complexes

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes

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