CD73 Attenuates Alcohol-Induced Liver Injury and Inflammation via Blocking TLR4/MyD88/NF-κB Signaling Pathway

Abstract

Background: Alcoholic liver disease (ALD) is liver damage caused by long-term drinking. Inflammation plays a central role in the progression of ALD. CD73 is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that is a key enzyme that converts ATP into adenosine. Evidence has shown that CD73 plays an important role in many diseases, but the role and mechanism of CD73 in alcohol-induced liver injury and inflammation is still unclear. Methods: The alcohol-induced liver injury and inflammation mouse model was established. The rAAV9-CD73 was used to overexpress CD73. Isolation of primary macrophages (MΦ) from the liver was conducted. The effects of CD73 on alcohol-induced liver injury and inflammation were evaluated by quantitative real-time PCR, Western blotting, ELISA, and immunohistochemical assay. Flow cytometry was used to detect the cell cycle and apoptosis. Results: Our results showed that overexpression of CD73 can reduce alcohol-induced liver damage, lipid accumulation, and the secretion of inflammatory cytokines. pEX3-CD73 can promote RAW264.7 cells proliferation and inhibit apoptosis via suppressing the activation of TLR4/MyD88/NF-κB signaling pathway. Inhibition of TLR4 further enhanced the antiinflammatory effect of overexpression of CD73. Conclusion: Overexpression of CD73 can reduce alcohol-induced liver injury and inflammation. CD73 may serve as a potential therapeutic target for ALD.

CD73/NT5E-mediated ubiquitination of AURKA regulates alcohol-related liver fibrosis via modulating hepatic stellate cell senescence

“…The results showed that the expression of CD39 and CD73 increased in the EtOH-fed+CCl 4 group from the second week. Interestingly, inhibition of CD39 or CD73 aggravated inflammation 37 , 38 . Based on the previous experimental results, we believe that the increase of CD39 and CD73 in early-fibrotic-stage was a body's self-protection to liver inflammation.…”

CD73, a significant protein in liver diseases

“…As a hydrolytic product of CD73, adenosine can perform cell protective and immunosuppressive functions through P1 receptors, thus terminating liver inflammation and promoting liver regeneration. In addition, CD73 can block the TLR4/MyD88/NF-κB signaling pathway ( 52 ), reduce the secretion of IL-6 and IL-1β, and delay the inflammatory process. In liver biopsies of NAFLD patients, CD73mRNA levels were significantly reduced ( 9 ), so CD73 knockout mice rarely developed fatty liver disease, or even progressed to steatohepatitis ( 13 ).…”

“…After CD73 deletion, adenosine production is reduced, resulting in the suppression of HSC activation and proliferation mediated by p2 receptor and decreased collagen expression, inhibiting the production of liver fibrosis. Meanwhile, inhibition of CD73 can promote HSC apoptosis and alleviate alcohol-induced liver fibrosis ( 52 ). Similarly, A2A adenosine receptor deficient mice were also protected from the effects of liver fibrosis by blocking the adenosine pathway ( 60 ).…”

Acetobacter pasteurianus BP2201 alleviates alcohol‐induced hepatic and neuro‐toxicity and modulate gut microbiota in mice

“…Metabolites and signalling molecules produced by gut microbes can impact nerve signalling and brain functions through several mechanisms such as the transportation of neurotransmitters or via circulation within the bloodstream (Wekerle, 2018 ). The equilibrium of gut microbiota can be disrupted by alcohol consumption, inducing dysbiosis (Brüssow, 2020 ) and a consequential overgrowth of deleterious microorganisms (Liu, Guo, et al, 2022 ; Liu, Vigorito, et al, 2022 ; Liu, Wu, et al, 2022 ). The toxins these microorganisms release can translocate across the intestinal mucosa, enter the bloodstream and breach the blood–brain barrier (Logsdon et al, 2018 ).…”