TLR4

TLR4 is a transmembrane pattern recognition receptor (PRR) expressed on macrophages, dendritic cells, and other innate immune cells. It recognizes lipopolysaccharide (LPS, endotoxin) found in the outer membrane of gram-negative bacteria. Recognition requires accessory proteins: LPS-binding protein (LBP) shuttles LPS to CD14, which then presents it to the TLR4/MD-2 complex. Ligand binding activates two main signaling pathways: (1) MyD88-dependent pathway, leading to rapid NF-κB activation and pro-inflammatory cytokine production (TNF-α, IL-1, IL-6, IL-8), and (2) TRIF-dependent pathway, leading to IRF3 activation and type I interferon production. Downstream NF-κB translocation to the nucleus upregulates genes for inflammatory mediators, adhesion molecules, and costimulatory molecules, bridging innate and adaptive immunity. Clinically, TLR4 signaling is a key driver of the systemic inflammatory response in gram-negative sepsis—excessive cytokine release (cytokine storm) contributes to vasodilation, capillary leak, hypotension, and disseminated intravascular coagulation (DIC) seen in septic shock. TLR4 also has roles beyond infection: it is implicated in sterile inflammation via recognition of damage-associated molecular patterns (DAMPs) like HMGB1 and heat shock proteins, atherosclerosis, and metabolic syndrome (linking free fatty acids to inflammation). Polymorphisms in TLR4 have been associated with variable susceptibility to sepsis and infection severity. This pathway is a target for research into sepsis therapeutics (e.g., anti-LPS or TLR4 antagonist strategies), though clinical translation has been limited. For boards, know that TLR4 = LPS/endotoxin receptor = gram-negative sepsis, NF-κB activation, and cytokine cascade (TNF-α, IL-1, IL-6).