Endogenous Regulation and Pharmacological Modulation of Sepsis-Induced HMGB1 Release and Action: An Updated Review

Zhu, Cassie Shu; Wang, Wei; Qiang, Xiaoling; Chen, Weiqiang; Lan, Xiqian; Li, Jianhua; Wang, Haichao

doi:10.3390/cells10092220

Cited by 15 publications

(14 citation statements)

References 194 publications

(282 reference statements)

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“…In response to hepatic I/R, liver resident Kupffer cells and infiltrated neutrophils orchestrate rigorous inflammatory responses manifested by the production of ROS, RNS, chemokines, and cytokines that collectively contribute to hepatic injury (1)(2)(3). Consequently, hepatocellular injury caused the passive release of DAMPs such as CIRP ( 5) and HMGB1 (6,7), which further stimulate a feed-forward cycle of inflammatory injuries (8, 9) (Figure 7). In response to injury, a neutrophilic CXC chemokine, MIP-2, can be produced by macrophages and hepatocytes, and facilitate neutrophil recruitment and activation (44).…”

Section: Discussionmentioning

confidence: 99%

“…This process exerts direct but moderate hepatic injury, and facilitates the infiltration of neutrophils, which release more ROS and proteases to exacerbate a cascade of inflammatory injury (2,3). Furthermore, the generation of ROS and RNS also leads to hepatocellular death (2,4) and consequent release of damageassociated molecular patterns (DAMPs) such as cold-inducible RNA-binding protein (CIRP) (5) and high mobility group box 1 (HMGB1) (6,7). We and others have shown that HMGB1 (8) and CIRP (9) exacerbate liver damage in animal models of hepatic I/R, as these DAMPs can amplify a cascade of oxidative and inflammatory responses during a late stage of reperfusion (1,10).…”

Section: Introductionmentioning

confidence: 99%

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Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion–Induced Local and Remote Inflammatory Injury

Qiang

Zhu

et al. 2022

Front. Immunol.

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BackgroundHepatic ischemia and reperfusion (I/R) injury is commonly associated with surgical liver resection or transplantation, and represents a major cause of liver damage and graft failure. Currently, there are no effective therapies to prevent hepatic I/R injury other than ischemic preconditioning and some preventative strategies. Previously, we have revealed the anti-inflammatory activity of a sweat gland-derived peptide, dermcidin (DCD), in macrophage/monocyte cultures. Here, we sought to explore its therapeutic potential and protective mechanisms in a murine model of hepatic I/R.MethodsMale C57BL/6 mice were subjected to hepatic ischemia by clamping the hepatic artery and portal vein for 60 min, which was then removed to initiate reperfusion. At the beginning of reperfusion, 0.2 ml saline control or solution of DCD (0.5 mg/kg BW) or DCD-C34S analog (0.25 or 0.5 mg/kg BW) containing a Cys (C)→Ser (S) substitution at residue 34 was injected via the internal jugular vein. For survival experiments, mice were subjected to additional resection to remove non-ischemic liver lobes, and animal survival was monitored for 10 days. For mechanistic studies, blood and tissue samples were collected at 24 h after the onset of reperfusion, and subjected to measurements of various markers of inflammation and tissue injury by real-time RT-PCR, immunoassays, and histological analysis.ResultsRecombinant DCD or DCD-C34S analog conferred a significant protection against lethal hepatic I/R when given intravenously at the beginning of reperfusion. This protection was associated with a significant reduction in hepatic injury, neutrophilic CXC chemokine (Mip-2) expression, neutrophil infiltration, and associated inflammation. Furthermore, the administration of DCD also resulted in a significant attenuation of remote lung inflammatory injury. Mechanistically, DCD interacted with epidermal growth factor receptor (EGFR), a key regulator of liver inflammation, and significantly inhibited hepatic I/R-induced phosphorylation of EGFR as well as a downstream signaling molecule, protein kinase B (AKT). The suppression of EGFR expression by transducing Egfr-specific shRNA plasmid into macrophages abrogated the DCD-mediated inhibition of nitric oxide (NO) production induced by a damage-associated molecular pattern (DAMP), cold-inducible RNA-binding protein, CIRP.ConclusionsThe present study suggests that human DCD and its analog may be developed as novel therapeutics to attenuate hepatic I/R-induced inflammatory injury possibly by impairing EGFR signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion–Induced Local and Remote Inflammatory Injury

Qiang

Zhu

et al. 2022

Front. Immunol.

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“…The spectrum of its functional facets is now largely extended ( 22 ). For example in the context of septic shock, its determinant impact has been early observed since HMGB1 injection was fatal whereas its neutralization by antibodies could rescue mice challenged with LPS ( 23 – 25 ). Extracellular HMGB1 is therefore recognized as one of the DAMPs which act as major mediators in immunity ( 26 ).…”

Section: Molecular Bases On Complement and Hmgb1 Multiple Functions W...mentioning

confidence: 99%

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

et al. 2022

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Our immune system responds to infectious (PAMPs) and tissue damage (DAMPs) signals. The complement system and alarmin High-Mobility Group Box 1 (HMGB1) are two powerful soluble actors of human host defense and immune surveillance. These systems involve molecular cascades and amplification loops for their signaling or activation. Initially activated as alarm raising systems, their function can be finally switched towards inflammation resolution, where they sustain immune maturation and orchestrate repair mechanisms, opening the way back to homeostasis. However, when getting out of control, these defense systems can become deleterious and trigger serious cellular and tissue damage. Therefore, they can be considered as double-edged swords. The close interaction between the complement and HMGB1 pathways is described here, as well as their traditional and non-canonical roles, their functioning at different locations and their independent and collective impact in different systems both in health and disease. Starting from these systems and interplay at the molecular level (when elucidated), we then provide disease examples to better illustrate the signs and consequences of their roles and interaction, highlighting their importance and possible vicious circles in alarm raising and inflammation, both individually or in combination. Although this integrated view may open new therapeutic strategies, future challenges have to be faced because of the remaining unknowns regarding the molecular mechanisms underlying the fragile molecular balance which can drift towards disease or return to homeostasis, as briefly discussed at the end.

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“…In addition to being located in the nucleus, HMGB1 can also be present in other organelles as well as in the extracellular space to regulate multiple cell processes ( Lotze and Tracey, 2005 ). Specifically, HMGB1 can be secreted or released by stressed, dead, or dying cells ( Wang et al, 1999 ; Scaffidi et al, 2002 ; Zhu et al, 2021 ; Chen et al, 2022 ). Once released, HMGB1 acts as a damage-associated molecular pattern (DAMP) to trigger immune responses by binding multiple pattern recognition receptors, such as toll-like receptor 4 (TLR4) and advanced glycosylation end product-specific receptor (AGER, also known as RAGE) ( Tsung et al, 2007 ; Kang et al, 2014a ; Amornsupak et al, 2022 ; He et al, 2022 ; Lei et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

HMGB1 is a mediator of cuproptosis-related sterile inflammation

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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Cuproptosis is a recently recognized modality of cell death driven by intracellular copper-dependent mitochondrial stress. However, the mediators of the sterile inflammatory response to cuproptotic death are undetermined. Here, we report that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern, is released by cuproptotic cells to initiate inflammation. Mechanically, copper accumulation-induced adenosine triphosphate (ATP) depletion activates AMP-activated protein kinase (AMPK) to promote HMGB1 phosphorylation, resulting in increased extracellular release. In contrast, genetic (using RNAi) or pharmacologic (using dorsomorphin) inhibition of AMPK activation limits cuproptosis and HMGB1 release. Functionally, the ability of HMGB1-deficient cuproptotic cells to promote advanced glycosylation end product-specific receptor (AGER, also known as RAGE)-dependent inflammatory cytokine production is greatly reduced. Thus, HMGB1 is a key immune mediator of cuproptosis-initiated sterile inflammation.

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Endogenous Regulation and Pharmacological Modulation of Sepsis-Induced HMGB1 Release and Action: An Updated Review

Cited by 15 publications

References 194 publications

Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion–Induced Local and Remote Inflammatory Injury

Human Dermcidin Protects Mice Against Hepatic Ischemia-Reperfusion–Induced Local and Remote Inflammatory Injury

Complement System and Alarmin HMGB1 Crosstalk: For Better or Worse

HMGB1 is a mediator of cuproptosis-related sterile inflammation

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