“An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein–protein interactions” (2025), by Ruiqin Luo et al. Immunology and Microbiology research paper. Original abstract below, unchanged. A free PDF is available.

An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein–protein interactions

Ruiqin Luo, Yi Yao, Zhuo Chen et al. · March 18, 2025 · Immunology and Microbiology

Abstract

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.

Free PDF DOI: 10.1186/s12964-025-02149-4