Lipopolysaccharide–Toll-like receptor 4–Nuclear factor kappa-light-chain-enhancer of activated B cells (Endotoxin–TLR4–NF-κB) signaling axis (Endotoxin–TLR4–NF-κB axis)

The Lipopolysaccharide–Toll-like receptor 4–Nuclear factor kappa-light-chain-enhancer of activated B cells (Endotoxin–TLR4–NF-κB) signaling axis is a fundamental pathway of the innate immune system responsible for detecting Gram-negative bacterial infections (Lu et al., 2008) [1]. The process begins when lipopolysaccharide (LPS), an endotoxin found in the outer membrane of Gram-negative bacteria, is recognized by the Toll-like receptor 4 (TLR4) complex, which requires co-receptors such as MD-2 and CD14 (Park & Lee, 2013) [2]. Activation of TLR4 triggers a downstream signaling cascade through MyD88-dependent or TRIF-dependent pathways, leading to the activation of the IκB kinase (IKK) complex (Ciesielska et al., 2021) [3]. This results in the phosphorylation and degradation of IκB proteins, allowing the transcription factor NF-κB to translocate into the nucleus and induce the expression of pro-inflammatory genes, including TNF-α, IL-6, and IL-1β (Liu et al., 2017) [4]. Dysregulation or overactivation of this axis is central to the pathogenesis of sepsis, chronic inflammatory diseases, and certain cancers (Kuzmich et al., 2017) [5]. Therapeutic strategies targeting this axis include TLR4 antagonists like Eritoran and TAK-242, as well as various inhibitors of the NF-κB pathway, aimed at mitigating excessive inflammation (Savva & Roger, 2013) [6].

Other names

LPS-TLR4-NF-kappaB pathwayToll-like receptor 4 signaling cascadeEndotoxin-induced TLR4 signalingTLR4/NF-kB axis

Antagonism of the Toll-like receptor 4 complex and subsequent inhibition of NF-kappaB nuclear translocation to prevent pro-inflammatory cytokine release (Savva & Roger, 2013) [6].