Platelets are circulating cellular sensors that express and release the damage-associated molecular pattern molecule (DAMP) high-mobility group box 1 (HMGB1) at sites of disrupted vascular and tissue integrity. We have recently identified platelet-derived HMGB1 as a critical mediator of thrombosis. The role of platelet-derived HMGB1 in mediating interactions with monocytes remains unknown. In trans genic mice with platelet-specific ablation of HMGB1 and neutralization studies, we show that HMGB1 derived from platelets promotes recruitment of monocytes and prevents monocytes from undergoing apoptosis. During experimental trauma and hemorrhagic shock, infiltrated monocytes in the lung and liver were significantly attenuated in mice lacking HMGB1 in platelets. Platelet-derived HMGB1 mediated monocyte migration via the receptor for advanced glycation end products (RAGE) and suppressed apoptosis via toll-like receptor 4 (TLR4)-dependent activation of MAPK/ERK (extracellular signal regulated kinase) in monocytes. In conclusion, we identify platelet-derived HMGB1 as a critical regulator of monocyte recruitment and apoptosis, with potential implications in disease states associated with thrombosis and inflammation. (C) 2016 Elsevier Inc. All rights reserved.