Erythrocytes as immunomodulators in trauma: orchestrating clearance pathways, inflammation, and organ injury

Abstract

Acute traumatic injury triggers complex systemic inflammatory and immune responses and remains a leading global cause of mortality and disability. Traditionally viewed primarily as passive oxygen carriers, erythrocytes are now emerging as key participants with significant immunomodulatory functions in the post-traumatic milieu. This narrative review presents a conceptual framework for understanding the evolving and dual-faceted role of erythrocytes in immune clearance pathways following acute injury. We focus on the known and hypothesized mechanisms by which erythrocytes actively modulate inflammatory responses, participate in clearing damage-associated substances, and influence tissue repair and systemic outcomes-processes achieved through surface molecule remodeling, the release of damage-associated molecular patterns (DAMPs), and dynamic interactions with immune cells. Importantly, we highlight that erythrocytes exert beneficial roles in homeostasis (e.g., regulated phagocytosis and immune complex shuttling) but can also become drivers of pathology when their clearance and activation pathways are dysregulated in the traumatic context. By integrating evidence from trauma patients, relevant animal models, and analogous pathological states, this review examines and synthesizes the novel and increasingly recognized roles of erythrocytes in traumatic immunopathology and provides a theoretical foundation for developing novel therapeutic strategies targeting erythrocyte function to improve patient outcomes.