Intracellular Hmgb1 Inhibits Inflammatory Nucleosome Release and Limits Acute Pancreatitis in Mice

Kang, Rui; Zhang, Liqun; Hou, Wen Chi; Yan, Zhenwen; Chen, Ruochan; Bonaroti, Jillian; Bansal, Preeti; Billiar, Timothy R.; Tsung, Allan; Wang, Q. Daniel; Bartlett, David L.; Whitcomb, David C.; Chang, Eugene B.; Zhu, Xiaorong; Wang, Haichao; Lü, Ben; Tracey, Kevin J.; Cao, Lizhi; Xue, Fan; Lotze, Michael T.; Zeh, Herbert J.; Tang, Daolin

doi:10.1053/j.gastro.2013.12.015

Cited by 182 publications

(183 citation statements)

References 56 publications

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“…HMGB1 has been reported as a major DAMP released during trauma 34 and presents at a high concentration in bone marrow. 35 To address whether HMGB1 mediates tissue damagesuppression of Mϕ necroptosis in response to LPS, we prepared HMGB1-deficient BCM from femurs and tibias harvested from inducible HMGB1-knockout mice 36 ( Figure 3a), and used the HMGB1-deficient BCM to treat BMDM. We found that HMGB1-deficient BCM failed to reduce LPS-induced BMDM necroptosis (Figure 3b To further confirm the role of HMGB1 in suppressing Mϕ necroptosis in response to LPS, BMDM were pretreated with recombinant HMGB1 for 12 h followed by LPS stimulation for…”

Section: Resultsmentioning

confidence: 99%

Tissue damage negatively regulates LPS-induced macrophage necroptosis

Scott

Fan

et al. 2016

Cell Death Differ

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Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mϕ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mϕ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mϕ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mϕ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.

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Section: Resultsmentioning

confidence: 99%

Tissue damage negatively regulates LPS-induced macrophage necroptosis

Scott

Fan

et al. 2016

Cell Death Differ

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“…Core histones H3 and H4 are most frequently reported to increase in plasma from sepsis patients as well as experimental sepsis and therapeutic administration of antibodies to these histones improve outcomes in these models 102, 129, 130. It is conceivable that histone citrullination as described above renders these less susceptible to degradation and easier to detect, creating a publication bias.…”

Section: Molecular Basis Of Histone‐related Cellular and Tissue Injurymentioning

confidence: 99%

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Szatmary

Huang

Criddle

et al. 2018

J Cellular Molecular Medi

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Histones are positively charged nuclear proteins that facilitate packaging of DNA into nucleosomes common to all eukaryotic cells. Upon cell injury or cell signalling processes, histones are released passively through cell necrosis or actively from immune cells as part of extracellular traps. Extracellular histones function as microbicidal proteins and are pro‐thrombotic, limiting spread of infection or isolating areas of injury to allow for immune cell infiltration, clearance of infection and initiation of tissue regeneration and repair. Histone toxicity, however, is not specific to microbes and contributes to tissue and end‐organ injury, which in cases of systemic inflammation may lead to organ failure and death. This review details the processes of histones release in acute inflammation, the mechanisms of histone‐related tissue toxicity and current and future strategies for therapy targeting histones in acute inflammatory diseases.

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“…Although the pathogenic mechanisms remain largely unknown, increasing evidence suggests that damageassociated molecular pattern molecules (DAMPs) play a central role in the pathogenesis of AP. DAMPs link local tissue damage to systemic inflammation response syndrome (SIRS), which, if severe or sustained, can lead to subsequent MOF and even death (9,11) (Figure 1). Most DAMPs are recognized by membrane-bound and cytosolic pattern recognition receptors (PRRs) expressed by both immune and nonimmune cell types.…”

Section: Introductionmentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

Self Cite

120

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The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

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Intracellular Hmgb1 Inhibits Inflammatory Nucleosome Release and Limits Acute Pancreatitis in Mice

Cited by 182 publications

References 56 publications

Tissue damage negatively regulates LPS-induced macrophage necroptosis

Tissue damage negatively regulates LPS-induced macrophage necroptosis

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Cell Death and DAMPs in Acute Pancreatitis

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