Journal Article

Deletion of TLR4 attenuates lipopolysaccharide-induced acute liver injury by inhibiting inflammation and apoptosis

Xiao, Xiao-chan, Li, Qian, Wu, Qi, Peng, You-you, Ren, Jun, Chen, Sai-nan, Tan, Ying, Dong, Mao-long

2021

Overview

Septic acute liver injury is one of the leading causes of fatalities in patients with sepsis. Toll-like receptor 4 (TLR4) plays a vital role in response to lipopolysaccharide (LPS) challenge, but the mechanisms underlying TLR4 function in septic injury remains unclear. In this study, we investigated the role of TLR4 in LPS-induced acute liver injury (ALI) in mice with a focus on inflammation and apoptosis. Wild-type (WT) and TLR4-knockout (TLR4 −/− ) mice were challenged with LPS (4 mg/kg) for 6 h. TLR4 signaling cascade markers (TLR4, MyD88, and NF-κB), inflammatory markers (TNFα, IL-1β, and IL-6), and apoptotic markers (Bax, Bcl-2, and caspase 3) were evaluated. We showed that LPS challenge markedly increased the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and other liver pathological changes in WT mice. In addition, LPS challenge elevated the levels of liver carbonyl proteins and serum inflammatory cytokines, upregulated the expression of TLR4, MyD88, and phosphorylated NF-κB in liver tissues. Moreover, LPS challenge significantly increased hepatocyte apoptosis, caspase 3 activity, and Bax level while suppressing Bcl-2 expression in liver tissues. These pathological changes were greatly attenuated in TLR4 −/− mice. Similar pathological responses were provoked in primary hepatic Kupffer cells isolated from WT and TLR4 −/− mice following LPS (1 μg/mL, 6 h) challenge. In summary, these results demonstrate that silencing of TLR4 attenuates LPS-induced liver injury through inhibition of inflammation and apoptosis via TLR4/MyD88/NF-κB signaling pathway. TLR4 deletion confers hepatoprotection against ALI induced by LPS, possibly by repressing macrophage inflammation and apoptosis.

• Publisher: Springer Singapore,Nature Publishing Group
• Subject: Alanine / Alanine transaminase / Animals / Apoptosis / Apoptosis - physiology / Aspartate aminotransferase / Bax protein / Bcl-2 protein / Biomedical and Life Sciences / Biomedicine / Carbonyl compounds / Caspase 3 - metabolism / Caspase-3 / Chemical and Drug Induced Liver Injury - metabolism / Chemical and Drug Induced Liver Injury - pathology / Cytokines - metabolism / Gene Knockout Techniques / Hepatocytes - metabolism / IL-1β / Immunology / Inflammation / Inflammation - metabolism / Interleukin 6 / Internal Medicine / Kupffer cells / Kupffer Cells - metabolism / Lipopolysaccharides / Liver / Liver - pathology / Macrophages / Medical Microbiology / Mice / Mice, Inbred C57BL / Mice, Knockout / MyD88 protein / Myeloid Differentiation Factor 88 - metabolism / NF-kappa B p50 Subunit - metabolism / NF-κB protein / Pharmacology/Toxicology / Rodents / Sepsis / Signal transduction / Signal Transduction - physiology / TLR4 protein / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - metabolism / Toll-like receptors / Tumor necrosis factor-α / Vaccine