The HMGB1-AGER-STING1 pathway mediates the sterile inflammatory response to alkaliptosis.

Alkaliptosis is a recently discovered form of regulated cell death driven by intracellular alkalization. However, the immune characteristics and mechanisms of alkaliptosis are still poorly understood. Here, we show that HMGB1, a multifunctional alarm protein that drives innate immunity, is necessary for inflammation caused by alkaliptotic damage. During alkaliptosis, HMGB1 translocation and release from the nucleus to the cytoplasm to the extracellular space requires nuclear DNA damage signals, whereas the FANCD2-dependent (but not ATM-mediated) DNA repair pathway inhibits this process. Once released by alkaliptotic cancer cells, extracellular HMGB1 binds to the AGER receptor in macrophages and then activates the STING1 pathway to produce pro-inflammatory cytokines (e.g., TNF and IL6). Consequently, the pharmacological or genetic inhibition of the HMGB1-AGER-STING1 pathway limits cytokine production during alkaliptosis. These findings provide new insight into the sterile inflammatory response to cell death.