MD-2 is required for disulfide HMGB1–dependent TLR4 signaling

Yang, Huan; Wang, Haichao; Zhang, Ju; Ragab, Ahmed; Lundbäck, Peter; Long, Wei; Valdés-Ferrer, Sergio; He, Mingzhu; Pribis, John P.; Li, Jianhua; Lü, Ben; Gerö, Domokos; Szabó, Csaba; Antoine, Daniel J.; Harris, Helena Erlandsson; Golenbock, D. T.; Meng, Jianmin; Roth, Jesse; Chavan, Sangeeta S.; Andersson, Ulf; Billiar, Timothy R.; Tracey, Kevin J.; Al‐Abed, Yousef

doi:10.1084/jem.20141318

Cited by 288 publications

(293 citation statements)

References 29 publications

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“…Disulfide HMGB1 mediates its effects via the TLR4/MD-2 complex. 13 A recent study using SW872 pre-adipocyte cell cultures showed that HMGB1 of undefined redox state bounds to RAGE but not to TLR4 and induced IL-6 and MCP-1 secretion. 4 Contrary to this study, we here showed that TLR4 is, at least, one of the receptors involved in the secretion of IL-6 from mature adipocytes following HMGB1 stimulation.…”

Section: Discussionmentioning

confidence: 99%

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

et al. 2016

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Chronic low grade inflammation is one of the major metabolic disorders in case of obesity and associated pathologies. By its important secretion function, the role of adipose tissue in this metabolic low grade inflammation is well known. Recently, it was demonstrated that the alarmin high mobility group box protein 1 (HMGB1) is involved in obesity-related pathologies by its increased serum levels in obese compared to normal weight individuals, and by its proinflammatory effects. However, the role of HMGB1 on adipocytes inflammation is poorly documented and we propose to investigate this point. Primary culture of human subcutaneous adipocytes were performed from human adipose tissue samples. Cells were treated with recombinant HMGB1 with/without anti-TLR4 antibody and inhibitors of NF-kB and P38 MAPK. Supernatants were collected for IL-6 and MCP-1 ELISA. HMGB1 initiates Toll-like receptor 4 (TLR4)-dependent activation of inflammation through the downstream NF-kB and P38 MAPK signaling pathway to upregulate the secretion of the pro-inflammatory cytokine IL-6. HMGB1 has proinflammatory effects on adipocytes. This reinforces the role of TLR4 in adipose tissue inflammation and antagonizing the HMGB1 inflammatory pathway could bring on new therapeutic targets to counteract obesity-associated pathologies.

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Section: Discussionmentioning

confidence: 99%

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

et al. 2016

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“…This antibody has been extensively characterized previously with respect to its HMGB1 neutralizing activity in in vitro and in vivo studies. The neutralizing activity of anti-HMGB1 monoclonal antibody (mAb) has been tested in cell culture assays, with both human and mouse macrophages, and in animal models of HMGB1-mediated damage, such as sepsis (8,(19)(20)(21)(22)(23)(24). Moreover, anti-HMGB1 mAb 2G7 has been shown to neutralize the cytokine isoform of HMGB1 (19).…”

Section: Neutralizing Anti-hmgb1 Antibodymentioning

confidence: 99%

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

Schaper

Timmeren

Petersen

et al. 2016

Mol Med

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High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 μg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.

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“…Once emitted into extracellular milieu, HMGB1 physically interacts with various receptors in immune cells. In particular, binding of HMGB1 to TLR4/MD2 complex plays a critical role in cytokine production (13,14). HMGB1-mediated proinflammatory cytokine production may further deteriorate organ dysfunction, and it has been established that the control of HMGB1 is crucial in the management of sepsis (6,15,16).…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…In search of TLR4 interacting substances other than LPS, which annexin A5 may interrupt, we looked in HMGB1, a late acting mediator, as a strong potential candidate. The critical role of TLR4 signaling in HMGB1-mediated cytokine release has been strongly supported by TLR4 knockout experiments in immune cells (13,14,36). In addition, HMGB1 is known to produce proinflammatory cytokines via the identical receptor complex (TLR4/MD2) as LPS (13,14,37).…”

Section: Annexin A5 Reduces Lps-and Hmgb1-mediated Pro-coagulation Inmentioning

confidence: 98%

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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MD-2 is required for disulfide HMGB1–dependent TLR4 signaling

Cited by 288 publications

References 29 publications

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice

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

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