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

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.

Toll-like receptor 5 tunes hepatic and pancreatic stellate cells activation

“…The transient inactivation of TLR5 was able to suppress the expression of the activating genes COL1A1 and ACTA2 and their encoded proteins, even after the administration of the most potent activator TGF-β. Even though in contrast with the previously observed effects of TLR5 in a mouse model of partial hepatectomy21 and hepatotoxin, cholestasis,20 the current study pointed to find the possible implication of TLR5 in TGF-β-mediated transactivation of stellate cells. Interestingly, a direct activation of TLR5 by the administration of flagellin20 21 inhibited the transactivation, which was prompted, instead, by the combination of TGF-β and TLR5 antagonist.…”

“…Even though in contrast with the previously observed effects of TLR5 in a mouse model of partial hepatectomy21 and hepatotoxin, cholestasis,20 the current study pointed to find the possible implication of TLR5 in TGF-β-mediated transactivation of stellate cells. Interestingly, a direct activation of TLR5 by the administration of flagellin20 21 inhibited the transactivation, which was prompted, instead, by the combination of TGF-β and TLR5 antagonist. The administration of wortmannin inhibited the expression of the transactivation proteins similarly to flagellin but did not modulate the expression of TLR5.…”

“…TLR5, activated by bacterial flagellin, is responsible for the induction of interleukin 1 receptor antagonist, thus ameliorating liver fibrosis 20. Nonetheless, TLR5 promotes liver regeneration in mice after partial hepatectomy 21. Gut microbiota dependent activation of TLR5 induces the synthesis of apolipoprotein A1 and high-density lipoprotein-cholesterol in the murine liver 22.…”

New Insights of OLFM2 and OLFM4 in Gut-Liver Axis and Their Potential Involvement in Nonalcoholic Fatty Liver Disease

“…Otherwise, TLR5 seems to play a key role in liver protection against intestinal dysbiosis-induced NAFLD in mice [56], preventing gut inflammation-related disorders [57]. Moreover, an increase in TLR5 seems to contribute to liver regeneration events [58]. Hence, in this case, the negative correlation of TLR5 with OLFM2 mRNA expression in the liver makes sense given that OLFM2 increases as NAFLD worsens, while TLR5 in the gut could be decreased due to the high inflammation pattern induced by intestinal dysbiosis and liver damage.…”

The State of the Hemocoagulation Link in the Hemostasis System of Mice After Partial Liver Resection Under Administration of Platelet Automesoconcentrate

“…Печінка -орган, який володіє високою здатністю до саморегенерації після її резекції, під час якої відбувається втрата великої кількості клітин паренхіми печінки [1]. Сьогодні все частіше застосовують резекцію печінки як один із методів лікування неракових захворювань печінки з наступним розвитком регенераційних процесів [2]. Після часткової гепатектомії регенераційні процеси включають три важливі фази: початкову, фазу проліферації та термінальну фазу [3].…”