Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms

Guo-qian, Chen; Li, Jianhua; Ochani, Mahendar; Rendon-Mitchell, B.; Qiang, Xiaoling; Susarla, Srinivas M.; Ulloa, Luis; Yang, Huan; Fan, Saijun; Goyert, Sanna M.; Wang, Ping; Tracey, Kevin J.; Sama, Andrew E.; Wang, Haichao

doi:10.1189/jlb.0404242

Cited by 171 publications

(138 citation statements)

References 42 publications

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“…Active secretion typically occurs not only in macrophages and monocytes (Chen et al, 2004;Kalinina et al, 2004), but also in nonimmune cells such as hepatocytes where it is overexpressed after hypoxia (Tsung et al, 2005). Here, we suggest that HMGB-1 is released from the ischemic brain parenchyma within 1 h after MCAO, based on early loss of HMGB-1 immunoreactivity in the striatum.…”

Section: Discussionmentioning

confidence: 70%

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Qiu

Nakagawa

Wang

et al. 2007

J Cereb Blood Flow Metab

371

299

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The nuclear protein high-mobility group box 1 (HMGB-1) promotes inflammation in sepsis, but little is known about its role in brain ischemia-induced inflammation. We report that HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, were expressed in normal brain and in cultured neurons, endothelia, and glial cells. During middle cerebral artery occlusion (MCAO), in mice, HMGB-1 immunostaining rapidly disappeared from all cells within the striatal ischemic core from 1 h after onset of occlusion. High-mobility group box 1 translocation from nucleus to cytoplasm was observed within the cortical periinfarct regions 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 predominantly translocated to the cytoplasm or disappeared in cells that colabeled with the neuronal marker NeuN. Furthermore, RAGE was robustly expressed in the periinfarct region after MCAO. Cellular release of HMGB-1 was detected by immunoblotting of cerebrospinal fluid as early as 2 h after ischemic reperfusion (2 h MCAO). High-mobility group box 1 released from neurons, in vitro, after glutamate excitotoxicity, maintained biologic activity and induced glial expression of tumor necrosis factor a (TNFa). Anti-HMGB-1 antibody suppressed TNFa upregulation in astrocytes exposed to conditioned media from glutamate-treated neurons. Moreover, TNFa and the cytokine intercellular adhesion molecule-1 increased in cultured glia and endothelial cells, respectively, after adding recombinant HMGB-1. In conclusion, HMGB-1 is released early after ischemic injury from neurons and may contribute to the initial stages of the inflammatory response.

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Section: Discussionmentioning

confidence: 70%

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Qiu

Nakagawa

Wang

et al. 2007

J Cereb Blood Flow Metab

371

299

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“…In addition to this HMGB1 antagonizing effect, we demonstrated in vivo that annexin A5 treatment reduced the serum HMGB1 level in LPS challenged mice ( Figure 4E). The active release of HMGB1 by immune cells is partially dependent on LPS-mediated TLR4 signaling (10,46). We speculate that annexin A5 potentially inhibits the release of HMGB1 by inhibiting both LPSand HMGB1-mediated TLR4 signaling.…”

Section: Discussionmentioning

confidence: 99%

Annexin A5 Increases Survival in Murine Sepsis Model by Inhibiting HMGB1-Mediated Proinflammation and Coagulation

Park

Jang

Choi

et al. 2016

Mol Med

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The identification of HMGB1 as a late mediator in sepsis has highlighted HMGB1 as a promising therapeutic target for sepsis treatment. Recent studies have revealed that annexin A5, a 35 kDa Ca 2+ -dependent phospholipid binding protein, exerts antiinflammatory effect by inhibiting LPS binding to TLR4/MD2 complex. Annexin A5 administration has been shown to protect against endotoxin lethality even when the treatment was given after the early cytokine response, which prompted our group to suspect that annexin A5 may inhibit the binding of HMGB1, as well as endotoxin, to TLR4. Here we suggest annexin A5 as a new inhibitor of HMGB1-mediated proinflammatory cytokine production and coagulation in sepsis. We first confirmed the inhibitory role of annexin A5 in LPS-induced production of proinflammatory cytokines both in vitro and in vivo. We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia in vivo. We then assessed the inhibiting role of annexin A5 in HMGB1/TLR4 interaction, and showed that annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNFα both in vitro and in vivo. Finally, we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated proinflammation and coagulation in patients with sepsis.

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“…Based on the above findings, it could be speculated that the LPS-induced early inflammatory cytokines may function as intermediating molecules in HMGB1 secretion through enhancing the hyperacetylation and phosphorylation of HMGB1. In contrast, several other reports showed that the inhibition of the early inflammatory cytokines or LPS signaling molecules did not significantly affect HMGB1 release (19,20). Thus, for the complete understanding of the HMGB1 release, the identification of additional molecules that are closely related to the event, but to date elusive, is necessary.…”

mentioning

confidence: 90%

Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway

Kim

Lee

et al. 2009

The Journal of Immunology

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Sepsis is a devastating condition characterized by a systemic inflammatory response. Recently, high mobility group box 1 (HMGB1) was identified as a necessary and sufficient mediator of the lethal systemic inflammation caused by sepsis. However, despite its clinical importance, the mechanism of HMGB1 release has remained to be elusive. In this study, we demonstrate that the IFN-β-mediated JAK/STAT pathway is essential for LPS or Escherichia coli-induced HMGB1 release, which is dependent on Toll/IL-1R domain-containing adapter-inducing IFN-β adaptor. Additionally, we show that NO acts as a downstream molecule of the IFN-β signaling. Furthermore, the JAK inhibitor treatment as well as the STAT-1 or IFN-β receptor deficiency reduced HMGB1 release in a murine model of endotoxemia. Our results suggest that HMGB1 release in sepsis is dependent on the IFN-β signaling axis; thus, therapeutic agents that selectively inhibit IFN-β signaling could be beneficial in the treatment of sepsis.

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Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms

Cited by 171 publications

References 42 publications

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

Annexin A5 Increases Survival in Murine Sepsis Model by Inhibiting HMGB1-Mediated Proinflammation and Coagulation

Bacterial Endotoxin Induces the Release of High Mobility Group Box 1 via the IFN-β Signaling Pathway

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