High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

Yang, Huan; Wang, Haichao; Chavan, Sangeeta S.; Andersson, Ulf

doi:10.2119/molmed.2015.00087

Cited by 294 publications

(251 citation statements)

References 51 publications

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“…Other plasma proteins that can bind HMGB1 and confer protection include thrombomodulin (38), soluble receptor for advanced glycation end products (s-RAGE) (39), and Siglec-10/CD24 (40). Our investigation does reveal a mechanism by which haptoglobin negatively modulates the proinflammatory properties of HMGB1, a critically important mediator of infection- and injury-elicited inflammatory diseases (10). …”

Section: Discussionmentioning

confidence: 96%

“…The inflammatory responses to infection and tissue inflammation are enhanced by exogenously derived pathogen-associated molecular pattern molecules (PAMPs), including bacterial peptidoglycan, endotoxin, and CpG-DNA, and by endogenously derived damage-associated molecular pattern molecules (DAMPs), including HMGB1 (3–9). HMGB1 is a central mediator of lethal infection and injury (5, 10). 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).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 96%

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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“…15 This current study sought to further elucidate the mechanisms involved in this hyperglycemia-induced trophoblast proinflammatory, antiangiogenic and antimigratory response. 19 Since the proinflammatory properties of HMGB1 are primarily mediated by TLR4, 19 and TLR2 activation triggers first trimester trophoblast apoptosis rather than inflammation, 20 we focused on TLR4. High-mobility group box-1 (HMGB1) is a DAMP that is elevated in pregnancies with preeclampsia 16,17 and with diabetes.…”

Section: Introductionmentioning

confidence: 99%

Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll‐Like receptor 4

Heim

Mulla

Potter

et al. 2018

American J Rep Immunol

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“…In addition, extracellular HMGB1 can play a critical role in the pathogenesis of inflammation with or without infection. Extracellular HMGB1 under various pathologic states is largely derived from a passive release pathway related to the death and decomposition of cells or an active pathway in live cells such as macrophages/monocytes [17-19]. HMGB1 is a DNA-binding protein that possesses cytokine-like, pro-inflammatory properties.…”

Section: Introductionmentioning

confidence: 99%

“…Cell surface receptors that engage in HMGB1 interaction include RAGE, TLR-4 and TLR-2. Macrophage activation by HMGB1 results in cytokine secretion; when released into the extracellular milieu, HMGB1, as a potent pro-inflammatory cytokine, activates a wide range of inflammatory responses, including massive production of chemokine adhesion molecules (e.g., ICAM-1, VCAM-1) and cytokines (e.g., TNF-α, IL-1β, NO) [16, 17, 20, 21]. In recent years, some experimental and clinical data have highlighted the contributions of extracellular HMGB1 to the pathogenesis of many inflammatory and cancer diseases.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Inflammatory Protein-2 in High Mobility Group Box 1 Secretion of Macrophage Cells Exposed to Lipopolysaccharide

Qin

Lou

Yang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Macrophage inflammatory protein-2 (MIP-2), a type of leukocyte chemokine, is primarily produced by macrophages, and levels increase significantly in early inflammation. However, the precise biological functions and mechanisms of MIP-2 in the development of inflammation remain unclear. The purposes of the present study were to investigate the role of MIP-2 in inflammation induced by lipopolysaccharide (LPS) in vitro and to determine the possibility of blocking the high mobility group box 1 (HMGB1) signalling pathway via MIP-2 inhibition. Methods: Macrophage cells (RAW264.7, U937 and THP-1 cells) were divided into control and treatments groups. Expression levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), HMGB1, chemokine (C-C motif) ligand-2 (Ccl-2), Toll-like receptor-4 (TLR-4), inducible nitric oxide synthase (iNOS), phosphorylated MAPKs (p38, ERKs, JNKs), PI3K/Akts, JAKs/STAT3, IκB, and cytoplasmic and nuclear NF-κB p65 in RAW264.7 cells were detected by qRT-PCR, enzyme-linked immunosorbent assay (ELISA) or western blot assays. Results: mip-2 siRNA and an anti-MIP-2 antibody significantly reduced the expression levels of Ccl-2, TLR-4, iNOS, IL-6, IL-1β, HMGB1, and TNF-α in RAW264.7 cells exposed to LPS (P<0.01). Additionally, mRNA expression levels of HMGB1 and TLR-4 in cells treated with LPS+mip-2 siRNA were significantly lower than those in cells treated with LPS alone (P<0.01 or P<0.05). The MIP-2 antibody significantly suppressed activation of p38-MAPK, p-STAT3, and p-Akts and translocation of NF-κB p65 from the cytoplasm to the nucleus in RAW264.7 exposed to LPS (P<0.01 or P<0.05). Conclusion: mip-2 siRNA and the MIP-2 antibody can reduce the inflammatory effects induced by LPS in macrophage cells. The mechanisms may occur through down-regulation of p38-MAPK, STAT3 and Akts phosphorylation and translocation of NF-κB p65. MIP-2 plays an important role in inflammation induced by LPS.

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High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule

Cited by 294 publications

References 51 publications

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

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

Excess glucose induce trophoblast inflammation and limit cell migration through HMGB1 activation of Toll‐Like receptor 4

Macrophage Inflammatory Protein-2 in High Mobility Group Box 1 Secretion of Macrophage Cells Exposed to Lipopolysaccharide

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