Luo Ruiqin, Yao Yuexin, Chen Zhuo, Sun Xiaoming
School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.
Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China.
Cell Commun Signal. 2025 Mar 18;23(1):142. doi: 10.1186/s12964-025-02149-4.
The LPS-TLR4 immune response is a critical mechanism in the body's defense against Gram-negative bacterial infections, yet its dysregulation can lead to severe inflammatory diseases. Lipopolysaccharide (LPS), a pivotal pathogen-associated molecular pattern (PAMP) on the surface of gram-negative bacteria, is recognized by Toll-like receptor 4 (TLR4), initiating a complex cascade of immune responses. This review delves into the intricate molecular structures and protein-protein interactions that underpin the LPS-TLR4 signaling pathway, offering a comprehensive analysis of both extracellular recognition and intracellular signal transduction. We explore the roles of key molecules such as LBP, CD14, MD-2, and TLR4 in the initial recognition of LPS, followed by the downstream signaling pathways mediated by MyD88-dependent and MyD88-independent mechanisms. The MyD88-dependent pathway primarily activates NF-κB and AP-1, leading to macrophage M1 polarization and the release of pro-inflammatory cytokines, while the MyD88-independent pathway triggers IRF activation and type-I interferon production. By elucidating the structural basis and functional interactions of these signaling molecules, this review not only enhances our understanding of the LPS-TLR4 immune response but also highlights its implications in both infectious and non-infectious diseases. Our findings underscore the potential of targeting this pathway for therapeutic interventions, offering new avenues for the treatment of inflammatory and immune-related disorders.
脂多糖- toll样受体4（LPS-TLR4）免疫反应是机体抵御革兰氏阴性菌感染的关键机制，但其失调可导致严重的炎症性疾病。脂多糖（LPS）是革兰氏阴性菌表面一种关键的病原体相关分子模式（PAMP），被Toll样受体4（TLR4）识别，引发一系列复杂的免疫反应。本文综述深入探讨了构成LPS-TLR4信号通路基础的复杂分子结构和蛋白质-蛋白质相互作用，对细胞外识别和细胞内信号转导进行了全面分析。我们探讨了关键分子如LBP、CD14、MD-2和TLR4在LPS初始识别中的作用，以及随后由MyD88依赖性和MyD88非依赖性机制介导的下游信号通路。MyD88依赖性途径主要激活NF-κB和AP-１，导致巨噬细胞M1极化和促炎细胞因子的释放，而MyD88非依赖性途径触发IRF激活和I型干扰素产生。通过阐明这些信号分子的结构基础和功能相互作用，本文综述不仅增强了我们对LPS-TLR4免疫反应的理解，还突出了其在感染性和非感染性疾病中的意义。我们的研究结果强调了针对该途径进行治疗干预的潜力，为治疗炎症和免疫相关疾病提供了新途径。
