Toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-kappaB) signaling pathway (TLR4-NF-kappaB pathway)

The Toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-kappaB) signaling pathway is a primary mediator of the innate immune response, responsible for detecting pathogens and initiating inflammatory cascades (PMID: 31035135). TLR4 is a cell-surface receptor that recognizes lipopolysaccharide (LPS) from Gram-negative bacteria, as well as various endogenous ligands associated with tissue damage (UniProt P33765). Upon activation, TLR4 recruits intracellular adapter proteins, primarily MyD88 and TRIF, which trigger a series of phosphorylation events culminating in the activation of the IkappaB kinase (IKK) complex (PMID: 20935648). This complex phosphorylates IkappaB, the inhibitory partner of NF-kappaB, leading to its degradation and allowing NF-kappaB to translocate into the nucleus to promote the transcription of pro-inflammatory genes such as TNF-alpha and IL-6 (PMID: 28130233). Dysregulation of this axis is central to the pathogenesis of sepsis, chronic inflammatory diseases, and certain malignancies (PMID: 30214617). Therapeutic strategies targeting this pathway include TLR4 antagonists like Eritoran and Tak-242, though their clinical use is often limited by the risk of systemic immunosuppression and impaired host defense (PMID: 23512811).

Other names

TLR4/NF-kappaB axisTLR4-mediated NF-kappaB activationLPS-TLR4-NF-kappaB signaling pathwayTLR4-NF-kB pathwayToll-like receptor 4-nuclear factor kappa B pathway

The pathway is targeted by inhibiting TLR4 ligand binding, blocking TLR4 intracellular signaling, or preventing the degradation of IkappaB to inhibit NF-kappaB nuclear translocation and subsequent pro-inflammatory gene expression (PMID: 23512811, PMID: 12496312).