High mobility group box 1–Toll-like receptor 4 signaling pathway (HMGB1–TLR4 pathway)

High mobility group box 1 (HMGB1) is a highly conserved nuclear protein that functions as a DNA chaperone, but when released into the extracellular environment by stressed or necrotic cells, it acts as a potent damage-associated molecular pattern (DAMP) (UniProt P09429). Extracellular HMGB1 binds to Toll-like receptor 4 (TLR4), a transmembrane protein that initiates innate immune responses (UniProt O00206). This binding triggers the recruitment of adapter proteins like MyD88, leading to the activation of the NF-κB signaling pathway and the massive release of pro-inflammatory cytokines such as TNF-α and IL-6 (PubMed: 25614314). The HMGB1–TLR4 axis is a central mediator in the cytokine storm associated with sepsis and is also implicated in chronic inflammatory conditions, autoimmune diseases, and the tumor microenvironment (PubMed: 31435104). Therapeutic interventions targeting this pathway include HMGB1-neutralizing antibodies, small molecule inhibitors like glycyrrhizin that bind directly to HMGB1, and TLR4 antagonists like TAK-242 (PubMed: 17210700, PubMed: 20406217). Modulating this pathway offers a strategy to dampen excessive inflammation without completely abolishing the host's ability to respond to pathogens, although the risk of immunosuppression remains a significant clinical concern (PubMed: 28935946).

Other names

HMGB1/TLR4 axisHMGB1-TLR4 signalingHigh mobility group box 1/Toll-like receptor 4 interactionHMGB1-TLR4-NF-κB pathway

Inhibition of HMGB1 release, neutralization of extracellular HMGB1, or antagonism of the TLR4 receptor to prevent downstream pro-inflammatory signaling.