<scp>DAMP</scp> molecular <scp>IL</scp>‐33 augments monocytic inflammatory storm in hepatitis B‐precipitated acute‐on‐chronic liver failure

Du, Xing; Shi, Yu; Yang, Ying; Yu, Yongsheng; Lou, Hua; Lv, Fang; Chen, Zhi; Yang, Qiao

doi:10.1111/liv.13503

Cited by 30 publications

(28 citation statements)

References 20 publications

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“…Although emerging evidence demonstrates that DAMPs released after the massive necrosis of hepatocytes contribute to the development of liver failure 11,32,33 , the potential role of extracellular gp96 in immune-mediated liver damage during liver failure has not been determined. Here, we first found that serum gp96 levels in patients with CHB and ACLF were elevated, which correlated with clinically relevant parameters in patients with ACLF, including ALT levels and the key pro-inflammatory cytokines TNF-α and IL-6.…”

Section: Discussionmentioning

confidence: 99%

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

Guan

Ding²,

Liu³

et al. 2020

Sci Rep

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Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acuteon-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus d-galactosamine (d-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/d-Galn-and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells.

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Section: Discussionmentioning

confidence: 99%

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

Guan

Ding²,

Liu³

et al. 2020

Sci Rep

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“…Seric IL-33 and ST2s concentrations are highly elevated compared to those in healthy donors and, interestingly enough, they are correlated with the severity of hepatic cytolysis (129, 130). In HBV acute-on-chronic liver failure (ACLF) (129), seric IL-33 and ST2s concentrations are pronouncedly higher than the concentrations observed in CHB patients. The circulating monocytes in ACLF patients present a highly activated and pro-inflammatory phenotype, which is correlated with IL-33 production.…”

Section: Contribution Of Il-1 Superfamily Of Cytokines To Hepatic Dismentioning

confidence: 96%

“…From this standpoint, IL-33 expression in LSEC significantly increases in patients with chronic HBV (CHB) infection, and is likewise highlighted in the hepatocytes of lesions/inflammatory foci in patients with the most severe form of hepatitis (129). Seric IL-33 and ST2s concentrations are highly elevated compared to those in healthy donors and, interestingly enough, they are correlated with the severity of hepatic cytolysis (129, 130). In HBV acute-on-chronic liver failure (ACLF) (129), seric IL-33 and ST2s concentrations are pronouncedly higher than the concentrations observed in CHB patients.…”

Section: Contribution Of Il-1 Superfamily Of Cytokines To Hepatic Dismentioning

confidence: 99%

Interleukin-1 Family Cytokines: Keystones in Liver Inflammatory Diseases

et al. 2019

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The pyrogenic property being the first activity described, members of the interleukin-1 superfamily (IL-1α, IL-1β, IL-18, and the newest members: IL-33, IL-36, IL-37, and IL-38) are now known to be involved in several inflammatory diseases such as obesity, atherosclerosis, cancer, viral and parasite infections, and auto-inflammatory syndromes as well as liver diseases. Inflammation processes are keystones of chronic liver diseases, of which the etiology may be viral or toxic, as in alcoholic or non-alcoholic liver diseases. Inflammation is also at stake in acute liver failure involving massive necrosis, and in ischemia-reperfusion injury in the setting of liver transplantation. The role of the IL-1 superfamily of cytokines and receptors in liver diseases can be either protective or pro-inflammatory, depending on timing and the environment. Our review provides an overview of current understanding of the IL-1 family members in liver inflammation, highlighting recent key investigations, and therapeutic perspectives. We have tried to apply the concept of trained immunity to liver diseases, based on the role of the members of the IL-1 superfamily, first of all IL-1β but also IL-18 and IL-33, in modulating innate lymphoid immunity carried by natural killer cells, innate lymphoid cells or innate T-αβ lymphocytes.

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“…Serum macrophage inflammatory protein 3 α levels also predict the severity of HB-ACLF [18]. Additionally, other inflammatory mediators, e.g., CXCL10 [19], extracellular histones [20], and DAMP molecular IL-33 [21], have been observed to closely relate with the prognosis of ACLF.…”

Section: Discussionmentioning

confidence: 99%

Increased Serum Soluble Urokinase Plasminogen Activator Receptor Predicts Short-Term Outcome in Patients with Hepatitis B-Related Acute-on-Chronic Liver Failure

Huang

Wang²,

Huang

et al. 2019

Gastroenterology Research and Practice

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Aims. Soluble urokinase plasminogen activator receptor (suPAR) reflects the immune activation in circumstances of inflammation and infection. It has been considered as a risk biomarker associated with poor outcome in various low-grade inflammation and infectious diseases. The study is aimed at investigating whether suPAR has a predictive value with short-term survival in patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Methods. Serum suPAR expression was compared among patients with different states of chronic hepatitis B virus infection. Sixty HB-ACLF patients were recruited as the training cohort and followed up for 90 days. Serum suPAR level and the clinical relevance with short-term outcome were investigated. The temporal dynamics of suPAR were evaluated in 50 HB-ACLF patients with available serum sequentially at baseline, week 2 and week 4. Another 167 HB-ACLF patients were enrolled to validate the predictive value of suPAR with respect to the prognosis. Results. Serum suPAR level was significantly increased in HB-ACLF patients compared to non-ACLF patients. In the training set of HB-ACLF, we observed higher suPAR level, INR, MELD score, and more complications in nonsurvivors than survivors. Longitudinal analysis revealed an increased trend of suPAR level in nonsurvivors during week 0 to week 4 and the modest decline in survivors. It showed that the synchronous suPAR level was higher in nonsurvivors at all indicated time points. Elevated suPAR level at baseline was identified as a strong predictor of a 90-day mortality of HB-ACLF patients. It was confirmed suPAR>16.26 ng/ml had a positive predictive value of 72.22% and a negative predictive value of 77.88% for poor outcome in the validation cohort. Conclusions. Serum suPAR level increases significantly in HB-ACLF patients and associated with a 90-day mortality. It suggests that suPAR might be a potential biomarker to predict the prognosis of HB-ACLF patients.

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DAMP molecular IL‐33 augments monocytic inflammatory storm in hepatitis B‐precipitated acute‐on‐chronic liver failure

Abstract: DAMP molecular IL-33 augmented the 'storm' of monocytic inflammation in response to LPS through ERK1/2 activation during HB-ACLF.

Cited by 30 publications

References 20 publications

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

Interleukin-1 Family Cytokines: Keystones in Liver Inflammatory Diseases

Increased Serum Soluble Urokinase Plasminogen Activator Receptor Predicts Short-Term Outcome in Patients with Hepatitis B-Related Acute-on-Chronic Liver Failure

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