High mobility group box 1–Toll-like receptor 4 inflammatory axis (HMGB1–TLR4 axis)

The High mobility group box 1–Toll-like receptor 4 (HMGB1–TLR4) inflammatory axis is a fundamental signaling pathway in the innate immune system that mediates the body's response to sterile injury and infection (NIH, 2020). HMGB1 is a highly conserved nuclear protein that functions as a DNA chaperone under normal conditions but acts as a potent damage-associated molecular pattern (DAMP) when released into the extracellular environment (Frontiers, 2020). Upon release, the disulfide isoform of HMGB1 binds to the TLR4/MD-2 complex on the surface of immune cells, such as macrophages and dendritic cells, triggering the NF-κB and MAPK signaling pathways (NIH, 2017). This activation leads to the robust production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which can drive systemic inflammation and tissue damage (MDPI, 2022). The axis is implicated in a wide range of pathologies, including sepsis, ischemia-reperfusion injury, autoimmune disorders, and neurodegenerative diseases (NIH, 2023). Therapeutic interventions targeting this axis, such as neutralizing antibodies, small molecule inhibitors like glycyrrhizin, and TLR4 antagonists, are being explored to mitigate hyper-inflammatory states while preserving essential immune functions (Frontiers, 2020).

Other names

HMGB1/TLR4 axisHMGB1–TLR4 signaling pathwayHMGB1–TLR4/MD-2 pathwayHigh mobility group box 1–Toll-like receptor 4 signaling

Drugs targeting this axis primarily work by neutralizing extracellular HMGB1, inhibiting its release from cells, or blocking its interaction with the TLR4/MD-2 receptor complex to prevent downstream pro-inflammatory signaling.