Extracellular high mobility group box 1 as a UV-induced alarmin driving cutaneous inflammation and photoaging via TLR4 signaling.

High mobility group box 1 (HMGB1) is a nuclear protein that functions as a damage-associated molecular pattern molecule upon extracellular release. It has an established role in sterile inflammation, yet its involvement in UV-induced human skin inflammation remains poorly characterized. This study investigated whether UV irradiation and chronic photoaging trigger HMGB1 release in human skin and whether this release drives proinflammatory cytokine expression and photoaging. Both acutely UV-irradiated and chronically photoaged human skin exhibited HMGB1 release, which temporally correlated with the upregulation of photoaging-related critical proinflammatory cytokines, IL-1β, IL-6, IL-8, and TNF-α. In cultured cells, UV irradiation reduced intracellular HMGB1 protein without altering mRNA levels while simultaneously increasing extracellular HMGB1 in supernatants, confirming active secretion rather than passive leakage. HMGB1 knockdown and blockade of TLR4, its principal receptor, significantly attenuated UV-induced proinflammatory cytokine expression in both cell types. In mouse skin, disruption of the HMGB1-TLR4 axis reduced neutrophil infiltration, suppressed cytokine expression, and mitigated dermal damage (photoaging). Collectively, these findings demonstrate that UV irradiation promotes active HMGB1 release from skin cells, amplifying cutaneous inflammation and exacerbating dermal damage via TLR4 signaling. Therapeutic targeting of the HMGB1-TLR4 axis therefore represents a promising strategy for mitigating UV-induced skin inflammation and its downstream pathologies, including photoaging.