In light of our recent finding that an HMGB1-neutralizing mAb (e.g., m2G7), capable of rescuing animals from lethal sepsis and acute liver injury could also inhibit HMGB1 endocytosis (32), we propose that therapeutic strategies capable of modulating HMGB1-mediated immune over-activation and/or associated immunosuppression could be developed in the clinical management of inflammatory diseases. Here, HMGB1 is linked to Sepsis.