Gene Number: 7099

Location: 9q33.1

Key Functions: Innate immune response, pathogen recognition, inflammation signaling

TLR4 encodes Toll-like receptor 4, a membrane-spanning pattern recognition receptor that serves as one of the immune system’s primary sentinels against microbial invasion. Highly expressed on macrophages, dendritic cells, and epithelial cells, TLR4 specializes in detecting lipopolysaccharides (LPS) — major components of the outer membrane of Gram-negative bacteria. Through this recognition, TLR4 acts as an early warning system, translating microbial presence into rapid immune activation.

Upon encountering LPS, TLR4 forms a receptor complex with MD-2 and CD14, initiating a powerful intracellular signaling cascade. This process activates two major transcriptional pathways: NF-κB, which drives the production of pro-inflammatory cytokines such as TNF-α and IL-6, and IRF3, which stimulates type I interferon synthesis. Together, these pathways orchestrate the innate immune response, promoting inflammation, leukocyte recruitment, and the activation of adaptive immunity.

TLR4’s function, however, is a double-edged sword. While it provides essential protection against bacterial pathogens, overactivation or dysregulation of this pathway can lead to hyperinflammation, septic shock, or contribute to chronic inflammatory diseases. Thus, tight regulation of TLR4 signaling is critical for maintaining immune equilibrium.

From a genetic standpoint, TLR4 polymorphisms such as Asp299Gly and Thr399Ile are of particular clinical significance. These variants alter receptor structure and LPS binding affinity, leading to interindividual differences in immune responsiveness. Carriers of these alleles may exhibit reduced LPS sensitivity, influencing susceptibility to sepsis, autoimmune conditions, atherosclerosis, and metabolic inflammation.

In summary, TLR4 stands as a genetic and molecular fulcrum of innate immunity — a receptor that bridges microbial detection with inflammatory defense. Its balance between activation and restraint determines whether the immune response protects the host or tips into pathology.