High mobility group box 1 (HMGB1)–Toll-like receptor 4 (TLR4)–Interleukin-23 (IL-23)–Interleukin-17A (IL-17A) inflammatory axis (HMGB1–TLR4–IL-23–IL-17A axis)

The HMGB1–TLR4–IL-23–IL-17A inflammatory axis is a critical signaling cascade that bridges innate and adaptive immunity to drive chronic inflammation and autoimmunity. High mobility group box 1 (HMGB1) acts as a damage-associated molecular pattern (DAMP) that, upon release from stressed or necrotic cells, binds to Toll-like receptor 4 (TLR4) on myeloid cells (UniProt P09429). This interaction triggers the production of Interleukin-23 (IL-23), which in turn promotes the differentiation and maintenance of Th17 cells (PMID: 24613304). These Th17 cells secrete Interleukin-17A (IL-17A), a potent pro-inflammatory cytokine that recruits neutrophils and induces the expression of other inflammatory mediators in various tissues (PMID: 12610626). This axis plays a pivotal role in the pathogenesis of several inflammatory conditions, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease (PMID: 31431610). Therapeutic strategies targeting this pathway involve the use of monoclonal antibodies to neutralize IL-23 or IL-17A, as well as small molecules or antibodies that inhibit HMGB1 or TLR4. While highly effective in reducing inflammation, modulating this axis carries risks of immunosuppression and increased susceptibility to opportunistic infections. Understanding the interplay between these components allows for more precise intervention in diseases characterized by dysregulated Th17-mediated responses.

Other names

HMGB1/TLR4/IL-23/IL-17A pathwayHMGB1-mediated Th17 responseHMGB1-TLR4-Th17 axis

Inhibition of HMGB1 release, blockade of TLR4 signaling, neutralization of IL-23, and antagonism of IL-17A or its receptor.