Circulating HMGB1 levels were found to be significantly elevated in children with sickle cell disease (SCD) and model animals, and the level was further increased in the occurrence of acute sickling events (vasoocclusive crises in humans or hypoxia/reoxygenation injury in mice), suggesting that HMGB1 plays a role in SCD‐mediated inflammation by activating TLR4.203. Here, TLR4 is linked to Schnyder corneal dystrophy.