scholarly journals Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Wen Zhang ◽  
Lei Wang ◽  
Xue-Hua Sun ◽  
Xian Liu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Early Gene ◽  
Hepatocyte Proliferation ◽  
Toll Like Receptor ◽  
Hepatic Lipid ◽  
Growth Factor Production ◽  
Toll Like Receptor 5 ◽  
Oil Red O ◽  
Tlr5 Expression

Abstract Background Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aimed to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration. Methods We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice, as a model of liver regeneration. Bacterial flagellin content was measured with ELISA, and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, we analyzed bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression with immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels, and with Western blotting analysis of hepatic NF-κB and STAT3 activation. Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. Results The bacterial flagellin content in the serum and liver increased, and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx. TLR5-deficient mice exhibited diminished numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokine and growth factor production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5−/− mice, as compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation, which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Furthermore, Tlr5−/− mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx. Conclusion We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.

scholarly journals Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

2020 ◽  
Author(s):  
Wen Zhang ◽  
Lei Wang ◽  
Xue-Hua Sun ◽  
Xian Liu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Growth Factors ◽  
Liver Regeneration ◽  
Quantitative Pcr ◽  
Early Gene ◽  
Immediate Early ◽  
Hepatocyte Proliferation ◽  
Hepatic Lipid ◽  
Oil Red O ◽  
Tlr5 Expression

Abstract BackgroundToll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating hepatic immune response and show hepatoprotective effect in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aims to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration.MethodsWe performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice as a model of liver regeneration. Bacterial flagellin content was measured by ELISA, and hepatic TLR5 expression was determined by quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression were analyzed by immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration was examined by quantitative PCR analyses of immediate early gene mRNA levels, and western blot analysis of hepatic NF-κB and STAT3 activation. Cytokines and growth factors production after PHx were detected using real-time PCR analyses and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.ResultsThe bacterial flagellin content in serum and liver was increased and the hepatic TLR5 expression was significantly up-regulated in WT mice upon PHx. TLR5-deficient mice exhibited reduced numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokines and growth factors production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5−/− mice compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Besides, Tlr5−/− mice displayed significantly decreased hepatic lipid concentrations and Oil Red O positive areas compared to control mice after PHx.ConclusionWe reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest a potential application of TLR5 agonist in promoting liver regeneration.

scholarly journals Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

2020 ◽  
Author(s):  
Wen Zhang ◽  
Lei Wang ◽  
Xue-Hua Sun ◽  
Xian Liu ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Real Time ◽  
Real Time Pcr ◽  
Early Gene ◽  
Hepatocyte Proliferation ◽  
Toll Like Receptor ◽  
Hepatic Lipids ◽  
Toll Like Receptor 5 ◽  
Oil Red O

Abstract Background Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating hepatic immune response and show hepatoprotective effect in mouse models of liver injury. However, the role of TLR5 in experimental models of liver regeneration has not been investigated. This study aims to determine the role of TLR5 in the partial hepatectomy (PHx)-induced liver regeneration. Methods We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice as an established model of liver regeneration. Bacterial flagellin content was measured by ELISA, and hepatic TLR5 expression was determined by real-time PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, proliferating cell nuclear antigen (PCNA) and the incorporation of bromodeoxyuridine (BrdU) were analyzed by immunohistochemistry (IHC) staining. The role of TLR5 in the priming of liver regeneration was examined by real-time PCR analyses of immediate early gene mRNA levels, as well as western blot analysis of hepatic NF-κB and STAT3 activation. Cytokines and growth factors production after PHx were detected using real-time PCR analyses and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipids concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. Results The bacterial flagellin content in serum and liver was increased and the hepatic TLR5 expression was significantly up-regulated in WT mice upon PHx. TLR5-deficient mice exhibited reduced numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokines and growth factors production. Moreover, PHx-induced NF-κB and STAT3 activation was inhibited in the liver of Tlr5−/− mice compared with WT mice. Consistently, administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation correlated with enhanced production of proinflammatory cytokines and recruitment of macrophages and neutrophils in liver. In addition, Tlr5−/− mice displayed significantly decreased hepatic lipids concentrations and Oil Red O positive areas compared with WT mice after PHx. Conclusions We reveal that TLR5 activation is involved in the initial events of liver regeneration after PHx. Our results demonstrate that TLR5 signaling positively regulates liver regeneration and suggest a potential application of TLR5 agonist in promoting liver regeneration.

scholarly journals F4/80+ Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2231
Author(s):  
Qingjun Lu ◽  
Hao Shen ◽  
Han Yu ◽  
Jing Fu ◽  
Hui Dong ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Serum Levels ◽  
Inhibitory Effect ◽  
Regenerative Process ◽  
Oncostatin M ◽  
Hepatocyte Proliferation ◽  
Initiation Phase ◽  
Distinct Role

The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80+ KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80+ KCs during the regenerative process. In RNA sequencing of isolated F4/80+ KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80+ KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80+ KCs in the initiation and progression phases of liver regeneration. F4/80+ KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80+ KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80+ KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.

scholarly journals The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5

2017 ◽  
Vol 13 (8) ◽  
pp. e1006574 ◽  
Author(s):  
Vida Forstnerič ◽  
Karolina Ivičak-Kocjan ◽  
Tjaša Plaper ◽  
Roman Jerala ◽  
Mojca Benčina
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 5

scholarly journals Toll-like receptor 5 in obesity: The role of gut microbiota and adipose tissue inflammation

Obesity ◽  
2015 ◽  
Vol 23 (3) ◽  
pp. 581-590 ◽  
Author(s):  
Satu Pekkala ◽  
Eveliina Munukka ◽  
Lingjia Kong ◽  
Eija Pöllänen ◽  
Reija Autio ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Gut Microbiota ◽  
Adipose Tissue Inflammation ◽  
Toll Like Receptor ◽  
Tissue Inflammation ◽  
Toll Like Receptor 5

scholarly journals The role of lncRNA MALAT1 in the regulation of hepatocyte proliferation during liver regeneration

2017 ◽  
Vol 39 (2) ◽  
pp. 347-356 ◽  
Author(s):  
Cuicui Li ◽  
Lei Chang ◽  
Zhiquan Chen ◽  
Zhongzhong Liu ◽  
Yanfeng Wang ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Hepatocyte Proliferation ◽  
Lncrna Malat1

scholarly journals Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

2013 ◽  
Vol 110 (20) ◽  
pp. E1857-E1866 ◽  
Author(s):  
L. G. Burdelya ◽  
C. M. Brackett ◽  
B. Kojouharov ◽  
I. I. Gitlin ◽  
K. I. Leonova ◽  
...  
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 5

scholarly journals Down-Regulation of Toll-Like Receptor 5 (TLR5) Increased VEGFR Expression in Triple Negative Breast Cancer (TNBC) Based on Radionuclide Imaging

2021 ◽  
Vol 11 ◽  
Author(s):  
Wen Jiang ◽  
Yeming Han ◽  
Ting Liang ◽  
Chao Zhang ◽  
Feng Gao ◽  
...  
Keyword(s):  
Triple Negative ◽  
Whole Body ◽  
Tumor Uptake ◽  
Toll Like Receptor ◽  
Rt Pcr ◽  
Down Regulation ◽  
Tumor Bearing ◽  
4T1 Cells ◽  
Toll Like Receptor 5 ◽  
Tlr5 Expression

In this study, GFP-tagged TNBC 4T1 cells with down-regulated TLR5 expression (TLR5− 4T1) and normal TLR5 expression (TLR5+ 4T1) were constructed, respectively. RT-PCR and Western blot studies showed that down-regulation of TLR5 obviously increased the expression of VEGFR in 4T1 cells. Highly stable radio-probes 125I-anti-TLR5 mAb/125I-VEGF/125I-IgG were obtained with labeling rates over 85% and radiochemical purities above 90%. Among these three probes, 125I−anti−TLR5 mAb and 125I-VEGF were used for specifically imaging TNBC, while 125I-IgG was used for comparison. Whole-body phosphorus autoradiography showed clear imaging at 48 h after injection of 125I-anti-TLR5 mAb and 125I-VEGF also provided clear imaging at 24 h. Biodistribution study demonstrated a higher tumor uptake of 125I-anti-TLR5 mAb in TLR5+ group compared with that in TLR5− group (P < 0.05), whereas tumor uptake of 125I-VEGF in TLR5+ group was lower than that in the TLR5− group (P < 0.05). Immunohistochemical staining suggested that the expression of TLR5 was lower, whereas the expression of VEGFR, CD31, and MVD (microvessel density) was higher in TLR5− tumor-bearing mice. In summary, the down-regulation of TLR5 in TNBC promoted the VEGFR expression and angiogenesis, resulting in the proliferation of TNBC cells. TLR5/VEGF might be a better indicator for monitoring the development of TNBC.

scholarly journals Lack of Multidrug Resistance-associated Protein 4 Prolongs Partial Hepatectomy-induced Hepatic Steatosis

2020 ◽  
Vol 175 (2) ◽  
pp. 301-311
Author(s):  
Ajay C Donepudi ◽  
Gregory J Smith ◽  
Oladimeji Aladelokun ◽  
Yoojin Lee ◽  
Steven J Toro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multidrug Resistance ◽  
Liver Injury ◽  
Liver Regeneration ◽  
Hepatic Steatosis ◽  
Partial Hepatectomy ◽  
Knockout Mice ◽  
Tissue Loss ◽  
Hepatocyte Proliferation ◽  
Hepatic Lipid

Abstract Multidrug resistance-associated protein 4 (Mrp4) is an efflux transporter involved in the active transport of several endogenous and exogenous chemicals. Previously, we have shown that hepatic Mrp4 expression increases following acetaminophen overdose. In mice, these increases in Mrp4 expression are observed specifically in hepatocytes undergoing active proliferation. From this, we hypothesized that Mrp4 plays a key role in hepatocyte proliferation and that lack of Mrp4 impedes liver regeneration following liver injury and/or tissue loss. To evaluate the role of Mrp4 in these processes, we employed two-third partial hepatectomy (PH) as an experimental liver regeneration model. In this study, we performed PH-surgery on male wildtype (C57BL/6J) and Mrp4 knockout mice. Plasma and liver tissues were collected at 24, 48, and 72 h postsurgery and evaluated for liver injury and liver regeneration endpoints, and for PH-induced hepatic lipid accumulation. Our results show that lack of Mrp4 did not alter hepatocyte proliferation and liver injury following PH as evaluated by Ki-67 antigen staining and plasma alanine aminotransferase levels. To our surprise, Mrp4 knockout mice exhibited increased hepatic lipid content, in particular, di- and triglyceride levels. Gene expression analysis showed that lack of Mrp4 upregulated hepatic lipin1 and diacylglycerol O-acyltransferase 1 and 2 gene expression, which are involved in the synthesis of di- and triglycerides. Our observations indicate that lack of Mrp4 prolonged PH-induced hepatic steatosis in mice and suggest that Mrp4 may be a novel genetic factor in the development of hepatic steatosis.

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