Splenic CD11clowCD45RBhigh dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failure

Zhang, Sainan; Yang, Naibin; Ni, Shun-Lan; Dong, Jin-Zhong; Shi, Chunwei; Li, Shanshan; Zhang, Shengguo; Tang, Xiaozhi; Lu, Mingqin

doi:10.1038/srep33206

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…All animal studies were approved by the Ethics Committee of Xi'an Jiaotong University. Mice in the model group were intraperitoneally injected with 10 g/kg LPS (Sigma-Aldrich, St. Louis, MO) and 800 mg/kg D-GalN (Sigma-Aldrich) as previously described (29), whereas mice in the control group were given saline instead. After 24 h, mice were euthanized for blood and liver tissue for further research.…”

Section: Methodsmentioning

confidence: 99%

Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure

Tian

Yao

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Liver sinusoids serve as the first line of defense against extrahepatic stimuli from the intestinal tract. Hepatic stellate cells (HSCs) are pericytes residing in the perisinusoidal space that integrate cytokine-mediated inflammatory responses in the sinusoids and relay these signals to the liver parenchyma. Oxidative stress has been shown to promote inflammation during acute liver failure (ALF). Whether and how oxidative stress is involved in HSC inflammation during ALF remains unclear. Level of systemic oxidative stress is reflected by superoxide dismutase (SOD). Thus, ALF patients were recruited to investigate the correlation between plasma SOD levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from ALF patients who had undergone liver transplantation. SOD2 expression and HSCs activation were investigated by immunohistochemistry. Inflammation, mitophagy, and apoptosis were investigated by immunoblot analysis and flow cytometry in HSCs treated with lipopolysaccharide (LPS) and reactive oxygen species (ROS) donors. The plasma SOD level was significantly increased in patients with ALF compared with those with cirrhosis (444.4 ± 23.58 vs. 170.07 ± 3.52 U/ml, P < 0.01) and was positively correlated with the Model for End-Stage Liver Disease-Na score ( R = 0.4720, P < 0.01). In vivo observations revealed that SOD2 immunostaining was increased in ALF patients and mice models, and in vitro experiments demonstrated that LPS/ROS promoted inflammation via inhibiting mitophagy. Moreover, the regulation of inflammation was apoptosis independent in HSCs. LPS-induced increases in oxidative stress promote inflammation through inhibiting mitophagy in HSCs during the process of ALF, providing a novel strategy for the treatment of patients with ALF. NEW & NOTEWORTHY Here we demonstrate that the serum superoxide dismutase (SOD) level is significantly increased in patients with acute liver failure (ALF), and, correlated with the Model for End-Stage Liver Disease-Na score, SOD level dropped in the remission stage of ALF. We identify that, in liver tissue from ALF patients and mice models, manganese-dependent SOD was overexpressed, and show lipopolysaccharide/HO inhibits mitophagy via reactive oxygen species in hepatic stellate cells (HSCs). We show that inhibited mitophagy promotes inflammation in HSCs, whereas mitophagy inducer rescues HSCs from lipopolysaccharide-induced inflammation.

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Section: Methodsmentioning

confidence: 99%

Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure

Tian

Yao

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Recently, tolerant DC infusion has been developed to induce Treg and inhibit inflammatory macrophages during inflammatory response. In our previous study, we demonstrated that the adoptive transfer of endotoxin tolerant DC into septic mice could reduce the secretion of inflammatory factors to relieve pathological injuries [ 12 , 51 ]. However, the immunomodulatory effect of tolerant DC infusion in clinical studies was not optimal, primarily due to the poor cell survival of tolerant DC in vivo.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy

Lin,

Lei,

Chai

et al. 2024

J Nanobiotechnol

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The utilization of extracellular vesicles (EV) in immunotherapy, aiming at suppressing peripheral immune cells responsible for inflammation, has demonstrated significant efficacy in treating various inflammatory diseases. However, the clinical application of EV has faced challenges due to their inadequate targeting ability. In addition, most of the circulating EV would be cleared by the liver, resulting in a short biological half-life after systemic administration. Inspired by the natural microvesicles (MV, as a subset of large size EV) are originated and shed from the plasma membrane, we developed the immunosuppressive MV-mimetic (MVM) from endotoxin tolerant dendritic cells (DC) by a straightforward and effective extrusion approach, in which DC surface proteins were inherited for providing the homing ability to the spleen, while αCD3 antibodies were conjugated to the MVM membranes for specific targeting of T cells. The engineered MVM carried a large number of bioactive cargos from the parental cells, which exhibited a remarkable ability to promote the induction of regulatory T cells (Treg) and polarization of anti-inflammatory M2 macrophages. Mechanistically, the elevated Treg level by MVM was mediated due to the upregulation of miR-155-3p. Furthermore, it was observed that systemic and local immunosuppression was induced by MVM in models of sepsis and rheumatoid arthritis through the improvement of Treg and M2 macrophages. These findings reveal a promising cell-free strategy for managing inflammatory responses to infections or tissue injury, thereby maintaining immune homeostasis.

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“…Lipopolysaccharide (LPS), also known as endotoxin, is a major component of the outer membrane of Gramnegative bacteria, which induces a strong inflammatory response [27,28]. D-gal is a toxin that depletes uracil nucleotides and triggers apoptosis and necrosis of hepatocytes to induce liver injury, which accompanied by LPS could further aggravate liver injury [29,30]. If the causative agent persists, it can progress to chronic liver Fig.…”

Section: Discussionmentioning

confidence: 99%

The dynamics of cell death patterns and regeneration during acute liver injury in mice

Shao

et al. 2022

FEBS Open Bio

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Acute liver injury is a serious clinical syndrome with multiple causes and unclear pathological process. Here, CCl4‐ and D‐galactosamine/lipopolysaccharide (D‐gal/LPS)‐induced acute liver injury was established to explore the cell death patterns and determine whether or not liver regeneration occurred. In CCl4‐induced hepatic injury, three phases, including the early, progressive, and recovery phase, were considered based on alterations of serum transaminases and liver morphology. Moreover, in this model, cytokines exhibited double‐peak fluctuations; apoptosis and pyroptosis persisted throughout all phases; autophagy occurred in the early and the progressive phases; and sufficient and timely hepatocyte regeneration was observed only during the recovery phase. All of these phenomena contribute to mild liver injury and subsequent regeneration. Strikingly, only the early and progressive phases were observed in the D‐gal/LPS model. Slight pyroptosis occurred in the early phase but diminished in the progressive phase, while apoptosis, reduced autophagy, and slight but subsequently diminished regeneration occurred only during the progressive phase, accompanied by a strong cytokine storm, resulting in severe liver injury with high mortality. Taken together, our work reveals variable modes and dynamics of cell death and regeneration, which lead to different consequences for mild and severe acute liver injury, providing a helpful reference for clinical therapy and prognosis.

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Splenic CD11clowCD45RBhigh dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failure

Cited by 6 publications

References 26 publications

Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure

Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure

Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy

The dynamics of cell death patterns and regeneration during acute liver injury in mice

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