A perspective on the role of extracellular hemoglobin on the innate immune system.

Host cell-derived danger-associated molecular patterns (DAMPs), such as the hemoglobin (Hb) can interact with the innate immune system either directly or through binding to pathogen-associated molecular patterns (PAMPs). Hemolysis occurs under various pathological conditions, leading to hemoglobinemia. In the extracellular environment, the Hb becomes a redox-reactive DAMP molecule. In severe hemolysis, the massive level of extracellular pro-oxidative Hb generates reactive oxygen species (ROS), which perturbs the innate immune homeostasis. The Hb also binds to PAMPs and triggers Toll-like receptor-mediated signal transduction. In this perspective, we review the roles of cell-free Hb in the innate immune system, focusing on the plausible interactions among Hb, pathogens, host cell components, and innate immune cells, all of which remain to be explored with experiential detail.