scholarly journals TLR4-NLRP3-GSDMD-Mediated Pyroptosis Plays an Important Role in Aggravated Liver Injury of CD38-/- Sepsis Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Huiqing Zhang ◽  
Yuna Du ◽  
Yujie Guo ◽  
Zeyu Wang ◽  
Hua Li ◽  
...  
Keyword(s):  
Liver Injury ◽  
Western Blot ◽  
Bacterial Infection ◽  
Hepatic Dysfunction ◽  
Bacterial Culture ◽  
Multiple Organ ◽  
Hematoxylin And Eosin ◽  
Bacterial Stimulation ◽  
Deficient Mice

Clinically, severe bacterial infection can cause septicemia and multiple organ dysfunction syndrome, especially liver injury. CD38 is closely related to many inflammatory pathways, but its role in liver injury caused by bacterial infection remains unclear. The purpose of this study is to discuss the specific role of CD38 in bacterial liver injury. Eight-week-old male C57BL/6 mice (WT, CD38-/- and CD38-/-TLR4mut) were used and stimulated with Escherichia coli (ATCC25922) or PBS, intraperitoneally. After 3 hours of bacterial stimulation, serum was collected to detect ALT and AST concentration, and liver tissue was harvested for hematoxylin and eosin staining and bacterial culture. The mRNA expressions of TLR4, NLRP3, IL-1β, IL-18, and GSDMD were quantitatively determined by RT-qPCR. The expressions of TLR4, MyD88, TRIF, NF-κB p65, NLRP3, GSDMD, and cytokines were detected by Western blot. The expression and localization of ERK1/2 were detected by immunohistochemistry and Western blot. The results showed that bacterial stimulation could upregulate the expression of inflammatory cytokines, leading to hepatic dysfunction. Moreover, bacterial stimulation of CD38-deficient mice can aggravate the inflammatory response, the expressions of TLR4, NF-κB, and ERK1/2 were significantly increased, and the biomarkers related to pyroptosis also manifested more obvious pyroptosis. However, TLR4 mutation significantly alleviated inflammation and pyroptosis in the liver caused by bacteria, on the basis of CD38 deficiency. Overall, CD38 knockout exacerbates bacteria-induced liver damage through TLR4-NLRP3-GSDMD-mediated pyroptosis.

scholarly journals Contribution of glutaredoxin-1 to Fas s-glutathionylation in ethanol-induced liver injury

2020 ◽  
Author(s):  
Xiaomin Sun ◽  
Qin Deng ◽  
Yunfei Zhang ◽  
Jingyu Chen ◽  
chunbao guo
Keyword(s):  
Liver Injury ◽  
Alcohol Exposure ◽  
Nuclear Factor Κb ◽  
Signaling Cascades ◽  
Alcoholic Liver Injury ◽  
Genetic Ablation ◽  
Induced Apoptosis ◽  
The Impact ◽  
Deficient Mice

Abstract Background The reversible glutathionylation modification (PSSG) of Fas augments apoptosis, which can be reversed by the cytosolic deglutathionylation enzyme glutaredoxin-1 (Grx1), but its roles in alcoholic liver injury remain unknown. Therefore, the objective of this study was to investigate the impact of genetic ablation of Grx1 on Fas-SSG in regulating ethanol-induced injury. Methods The role of Grx1 in alcoholic liver injury was investigated in Grx1 knockout mice. Alcoholic liver injury was achieved by feeding mice with a liquid diet containing 5% ethanol for 2 weeks. Results We demonstrated that ethanol-fed mice had increased Grx1 activity and oxidative damage in the liver. On the other hand, Grx1-deficient mice had more serious liver damage when exposed to ethanol compared to that of wild-type mice, accompanied by increased alanine aminotransferase and aspartate aminotransferase levels, Fas-SSG, cleaved caspase-3 and hepatocyte apoptosis. Grx1 ablation resulted in the suppression of ethanol-induced nuclear factor-κB (NF-κB) signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-κB prevented Fas-induced apoptosis in WT mice but not Grx1-/- mice. Furthermore, the number of Kupffer cells and related proinflammatory cytokines, including Akt, were lower in Grx1-/- livers than those of the controls. Conclusions Grx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.

scholarly journals The role of the Siglec-G ITIM domain during bacterial infection

2022 ◽  
Vol 67 (4) ◽  
pp. 163-169
Author(s):  
Yin Wu ◽  
Darong Yang ◽  
Guo-Yun Chen
Keyword(s):  
Western Blot ◽  
Bacterial Infection ◽  
Expression Vectors ◽  
Immunoglobulin Superfamily ◽  
Western Blot Assay ◽  
Downstream Signaling ◽  
Sialic Acid Binding ◽  
Associated Proteins ◽  
Membrane Bound

Siglecs, membrane-bound lectins of the sialic acid-binding immunoglobulin superfamily, inhibit immune responses by recruiting tyrosine phosphatases (e.g., SHP-1 and SHP-2) through their cytoplasmic immunoreceptor tyrosine-based inhibition motif (ITIM) domain. The role of Siglecs in infection has been extensively studied, but downstream signaling through the ITIM domain remains unclear. Here, we used a GST pull-down assay to identify additional proteins associated with the ITIM domain during bacterial infection. Gdi2 bound to ITIM under normal homeostasis, but Rab1a was recruited to ITIM during bacterial infection. Western blot analysis confirmed the presence of SHP-1 and SHP-2 in eluted ITIM-associated proteins under normal homeostasis. We confirmed the association of ITIM with Gdi2 or Rab1a by transfection of corresponding expression vectors in 293T cells followed by immunoprecipitation-western blot assay. Thus, ITIM’s role in the inhibition of the immune response during bacterial infection may be regulated by interaction with Gdi2 and Rab1a in addition to SHP-1 and SHP-2.

scholarly journals Aggravated Liver Injury but Attenuated Inflammation in PTPRO-Deficient Mice Following LPS/D-GaIN Induced Fulminant Hepatitis

2015 ◽  
Vol 37 (1) ◽  
pp. 214-224 ◽  
Author(s):  
Xiaochen Wang ◽  
Shushan Yan ◽  
Donghua Xu ◽  
Jun Li ◽  
Yu Xie ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fulminant Hepatitis ◽  
Feedback Regulation ◽  
Adaptive Immune ◽  
Hepatic Cells ◽  
Ifn Γ ◽  
Deficient Mice

Background/Aims: Critical roles of PTPRO and TLR4 have been implicated in hepatocellular carcinoma. However, little is known about their modifying effects on inflammation-related diseases in liver, particularly fulminant hepatitis (FH). We aim to investigate the potential role of PTPRO and its interaction with TLR4 in LPS/D-GaIN induced FH. Methods: A LPS/D-GaIN induced mouse FH model was used. RAW264.7 cells were transfected with PTPRO over-expressed lentiviral plasmids for further investigation. Results: The mortality of PTPRO KO mice is higher than WT mice after LPS/D-GaIN administration. Aggravated liver injury was demonstrated by increased level of serous ALT and AST and numerous hepatic cells death in PTPRO KO mice following LPS/D-GaIN administration. Interestingly, inflammation was attenuated in PTPRO-deficient mice following LPS/D-GaIN administration, which was suggested by decreased inflammatory cytokines (TNF-a, IFN-γ, IL-1ß, IL-6, IL-17A and IL-12) and cells infiltrating into spleen (CD3+IFN-γ+ cells, CD3+TNF-a+ cells, F4/80+/TLR4+ cells). A feedback regulation between PTPRO and TLR4 dependent on NF-γB signaling pathway was demonstrated in vivo and in vitro. Conclusion: PTPRO plays an important role in FH by interacting with TLR4. The crosstalk between PTPRO and TLR4 is a novel bridge linking innate immune and adaptive immune in acute liver injury.

scholarly journals Differential expression of Lutheran/BCAM regulates biliary tissue remodeling in ductular reaction during liver regeneration

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yasushi Miura ◽  
Satoshi Matsui ◽  
Naoko Miyata ◽  
Kenichi Harada ◽  
Yamato Kikkawa ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Critical Role ◽  
Disease Models ◽  
Distinct Mode ◽  
Ductular Reaction ◽  
Deficient Mice ◽  
Injured Liver

Under chronic or severe liver injury, liver progenitor cells (LPCs) of biliary origin are known to expand and contribute to the regeneration of hepatocytes and cholangiocytes. This regeneration process is called ductular reaction (DR), which is accompanied by dynamic remodeling of biliary tissue. Although the DR shows apparently distinct mode of biliary extension depending on the type of liver injury, the key regulatory mechanism remains poorly understood. Here, we show that Lutheran (Lu)/Basal cell adhesion molecule (BCAM) regulates the morphogenesis of DR depending on liver disease models. Lu+ and Lu- biliary cells isolated from injured liver exhibit opposite phenotypes in cell motility and duct formation capacities in vitro. By overexpression of Lu, Lu- biliary cells acquire the phenotype of Lu+ biliary cells. Lu-deficient mice showed severe defects in DR. Our findings reveal a critical role of Lu in the control of phenotypic heterogeneity of DR in distinct liver disease models.

scholarly journals Differential Role of Rapamycin in Epidermis-Induced IL-15-IGF-1 Secretion via Activation of Akt/mTORC2

2017 ◽  
Vol 42 (5) ◽  
pp. 1755-1768 ◽  
Author(s):  
Yang Bai ◽  
Rui Xu ◽  
Xueyuan Zhang ◽  
Xiaorong Zhang ◽  
Xiaohong Hu ◽  
...  
Keyword(s):  
Wound Healing ◽  
Western Blot ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Low Dose ◽  
Underlying Mechanism ◽  
High Dose ◽  
Mtorc1 Pathway ◽  
Hematoxylin And Eosin

Backgroud/Aims: The effects of rapamycin (RPM) on wound healing have been previously studied. However, reciprocal contradictory data have been reported, and the underlying mechanism remains unclear. This study aims to uncover differential role of RPM in regulation of wound healing and explore the possible mechanism. Methods: C57BL/6J mice and epidermal cells were treated with different doses of RPM. The wound re-epithelialization was observed by hematoxylin and eosin (HE) staining. The expression of IL-15 and IGF-1 were detected by immunohistochemistry and quantitative real-time PCR. Epidermal cell survival was determined by CCK-8 assays. Moreover, the mTORC1 and mTORC2 pathway were examined by western blot analysis. Results: This study showed that differential doses of RPM could lead to separate consequences in epidermis. Histological analyses showed that low-dose RPM promoted wound healing, and enhanced the expression of IL-15 and IGF-1. Furthermore, western blot analysis showed that the effect of low-dose RPM in epidermis were not through mTORC1 pathway. Instead, activation of the Akt/mTORC2 pathway was involved in low-dose RPM-induced IL-15 and IGF-1 production in epidermis, while high-dose RPM inhibited the expression of IL-15 and IGF-1 and the activity of mTORC1 and mTORC2 pathway. Conclusion: This study for the first time demonstrated that RPM-mediated wound healing was dose-dependent.

scholarly journals Beyond Metabolism: Role of the Immune System in Hepatic Toxicity

2020 ◽  
Vol 39 (2) ◽  
pp. 151-164
Author(s):  
Kenneth L. Hastings ◽  
Martin D. Green ◽  
Bin Gao ◽  
Patricia E. Ganey ◽  
Robert A. Roth ◽  
...  
Keyword(s):  
Immune System ◽  
Liver Injury ◽  
Bacterial Infection ◽  
Immune Cells ◽  
Bacterial Infections ◽  
Hepatic Toxicity ◽  
Drug Induced ◽  
Host Immune Responses ◽  
Disease Spectrum

The liver is primarily thought of as a metabolic organ; however, the liver is also an important mediator of immunological functions. Key perspectives on this emerging topic were presented in a symposium at the 2018 annual meeting of the American College of Toxicology entitled “Beyond metabolism: Role of the immune system in hepatic toxicity.” Viral hepatitis is an important disease of the liver for which insufficient preventive vaccines exist. Host immune responses inadequately clear these viruses and often potentiate immunological inflammation that damages the liver. In addition, the liver is a key innate immune organ against bacterial infection. Hepatocytes and immune cells cooperatively control systemic and local bacterial infections. Conversely, bacterial infection can activate multiple types of immune cells and pathways to cause hepatocyte damage and liver injury. Finally, the immune system and specifically cytokines and drugs can interact in idiosyncratic drug-induced liver injury. This rare disease can result in a disease spectrum that ranges from mild to acute liver failure. The immune system plays a role in this disease spectrum.

scholarly journals A Critical Role of Natural Immunoglobulin M in Immediate Defense Against Systemic Bacterial Infection

1998 ◽  
Vol 188 (12) ◽  
pp. 2381-2386 ◽  
Author(s):  
Marianne Boes ◽  
Andrey P. Prodeus ◽  
Tara Schmidt ◽  
Michael C. Carroll ◽  
Jianzhu Chen
Keyword(s):  
Bacterial Infection ◽  
Bacterial Load ◽  
Critical Role ◽  
Cecal Ligation ◽  
Immunoglobulin M ◽  
Mouse Serum ◽  
Microbial Infection ◽  
Acute Peritonitis ◽  
Deficient Mice

To evaluate the role of natural immunoglobulin (Ig)M in the immediate response against microbial infection, we tested mutant mice that are deficient in secreted (s)IgM in an acute peritonitis model induced by cecal ligation and puncture (CLP). 20% of wild-type mice died within 32 h of CLP, whereas 70% of sIgM-deficient mice died within the same time period. The increased susceptibility was associated with a reduced level of tumor necrosis factor (TNF)-α, a decreased neutrophil recruitment and an increased bacterial load in the peritoneum, and elevated levels of endotoxin and proinflammatory cytokines in the circulation. Resistance to CLP by sIgM-deficient mice was restored by reconstitution with polyclonal IgM from normal mouse serum. Reconstitution with a monoclonal IgM specific to phosphatidylcholine, a conserved cell membrane component, has a modest effect but a monoclonal IgM specific to phosphocholine is not protective. These findings demonstrate a critical role of natural IgM in the immediate defense against severe bacterial infection.

scholarly journals Histone methyltransferase G9a protects against acute liver injury through GSTP1

2019 ◽  
Vol 27 (4) ◽  
pp. 1243-1258 ◽  
Author(s):  
Yu Zhang ◽  
Weili Xue ◽  
Wenquan Zhang ◽  
Yangmian Yuan ◽  
Xiuqin Zhu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Damage ◽  
Acute Liver Injury ◽  
Epigenetic Modification ◽  
Histone Methyltransferase ◽  
Methyltransferase Activity ◽  
Detoxifying Enzymes ◽  
Apap Overdose ◽  
Deficient Mice

Abstract Acute liver injury is commonly caused by bacterial endotoxin/lipopolysaccharide (LPS), and by drug overdose such as acetaminophen (APAP). The exact role of epigenetic modification in acute liver injury remains elusive. Here, we investigated the role of histone methyltransferase G9a in LPS- or APAP overdose-induced acute liver injury. Under d-galactosamine sensitization, liver-specific G9a-deficient mice (L-G9a−/−) exhibited 100% mortality after LPS injection, while the control and L-G9a+/− littermates showed very mild mortality. Moreover, abrogation of hepatic G9a or inhibiting the methyltransferase activity of G9a aggravated LPS-induced liver damage. Similarly, under sublethal APAP overdose, L-G9a−/− mice displayed more severe liver injury. Mechanistically, ablation of G9a inhibited H3K9me1 levels at the promoters of Gstp1/2, two liver detoxifying enzymes, and consequently suppressed their transcription. Notably, treating L-G9a−/− mice with recombinant mouse GSTP1 reversed the LPS- or APAP overdose-induced liver damage. Taken together, we identify a novel beneficial role of G9a-GSTP1 axis in protecting against acute liver injury.

scholarly journals Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration

Biology ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 19
Author(s):  
Karuna Rasineni ◽  
Serene M. L. Lee ◽  
Benita L. McVicker ◽  
Natalia A. Osna ◽  
Carol A. Casey ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Failure ◽  
Liver Damage ◽  
Asialoglycoprotein Receptor ◽  
Fulminant Liver Failure ◽  
Wild Type ◽  
Tissue Samples ◽  
Tnf Α ◽  
Deficient Mice

Background: Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. Methods: Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.

The Protective Effects of Protease Inhibitor MG-132 on Sepsis-Induced Acute Kidney Injury and Its Mechanisms

2021 ◽  
Vol 11 (2) ◽  
pp. 265-270
Author(s):  
Xiaobo Zhang ◽  
Ying Zhu ◽  
Ying Zhou ◽  
Bingru Fei
Keyword(s):  
Acute Kidney Injury ◽  
Western Blot ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Effects ◽  
Serum Cystatin C ◽  
Hematoxylin And Eosin ◽  
Underlying Mechanisms ◽  
Control Sham

MG-132 is an aldehyde peptide proteasome inhibitor, which reduces the inflammatory response and exerts a protective effect on severe acute pancreatitis and associated lung injury of rats. However, the involvement of MG-132 in sepsis-induced acute kidney injury (AKI) and the underlying mechanisms remain unknow. In this study, SD rats were employed to induce sepsis by cecal ligation and puncture (CLP) method and then divided into control, sham, CLP, and CLP + MG-132. Histopathology observation was detected by hematoxylin and eosin staining. The levels of biomarkers representing renal function such as serum creatinine (Scr), blood urea nitrogen (BUN), serum cystatin C (Scys C), and indicators of AKI such as Kim-1, IL-18, α glutathione S-traferase (α-GST) and albumin were measured by ELISA. Western blot and immunohistochemistry were performed to measure Testican-1. In order to assess the role of Testican-1, the expression of β-catenin, c-myc and cyclinD1 were evaluated by western blot. The results indicated that the levels of SCr, BUN, Scys C, KIM-1, IL-18, GST-α and albumin were decreased after MG-132 treatment compared with CLP group. And both pathological injury and W/D ratio were obviously improved in the CLP + MG- 132 group. Furthermore, the level of Testican-1 increased in the CLP group while a decreased presented in the CLP + MG-132 group. The expression of β-catenin, c-myc and cyclinD1 were downregulated in the CLP + MG-132 group compared to the CLP group. Our findings suggested that MG-132 can protect against AKI via inhibiting Testican-1 through the Wnt/β-catenin pathway MG-132 served as a novel biomarker and therapeutic regimen for sepsis-induced AKI.

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