Tlr4, a member of the Toll-like receptor (TLR) family, is a transmembrane receptor that plays a central role in the innate immune response. It recognizes lipopolysaccharide (LPS) or bacterial endotoxins, initiating intracellular signaling cascades. Through adaptor proteins like MyD88 and TRIF, Tlr4 activates transcription factors NF-κB and AP-1, leading to the up-regulation of pro-inflammatory cytokines and increased interferon expression respectively. Dysregulation of Tlr4 is associated with numerous diseases, highlighting its biological importance [1,2].

In septic acute liver injury, deletion of Tlr4 in TLR4-knockout (TLR4-/-) mice attenuated lipopolysaccharide (LPS)-induced acute liver injury. LPS challenge in wild-type (WT) mice led to increased serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, elevated liver carbonyl proteins and serum inflammatory cytokines, up-regulated Tlr4, MyD88, and phosphorylated NF-κB, and increased hepatocyte apoptosis. These pathological changes were greatly reduced in TLR4-/-mice, suggesting that Tlr4 deletion confers hepatoprotection against ALI by inhibiting inflammation and apoptosis via the TLR4/MyD88/NF-κB signaling pathway [3].

In conclusion, Tlr4 is crucial for the innate immune response, with its hyperactivation linked to various diseases. Gene knockout studies, such as the TLR4-/-mouse model, have revealed its role in specific disease conditions like septic acute liver injury. Understanding Tlr4's functions through such models provides insights into the underlying mechanisms of diseases and potential therapeutic targets.

References:

1. Zhang, Yongsheng, Liang, Xinjie, Bao, Xuefei, Xiao, Wei, Chen, Guoliang. 2022. Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective. In European journal of medicinal chemistry, 235, 114291. doi:10.1016/j.ejmech.2022.114291. https://pubmed.ncbi.nlm.nih.gov/35307617/

2. Kim, Hyo-Jin, Kim, Hyemin, Lee, Jeong-Hyung, Hwangbo, Cheol. 2023. Toll-like receptor 4 (TLR4): new insight immune and aging. In Immunity & ageing : I & A, 20, 67. doi:10.1186/s12979-023-00383-3. https://pubmed.ncbi.nlm.nih.gov/38001481/

3. Chen, Sai-Nan, Tan, Ying, Xiao, Xiao-Chan, Ren, Jun, Dong, Mao-Long. 2021. Deletion of TLR4 attenuates lipopolysaccharide-induced acute liver injury by inhibiting inflammation and apoptosis. In Acta pharmacologica Sinica, 42, 1610-1619. doi:10.1038/s41401-020-00597-x. https://pubmed.ncbi.nlm.nih.gov/33495514/