The field of red cell biology is undergoing a quiet revolution. Long assumed to be inert oxygen carriers, RBCs are emerging as important modulators of the innate immune response. Erythrocytes bind and scavenge chemokines, nucleic acids, and pathogens in circulation. Depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. We examine erythrocyte immune function through a comparative and evolutionary lens, as this framework may offer perspective into newly recognized roles of human RBCs. Next, we review the known immune roles of human RBCs and discuss their activity in the context of sepsis where erythrocyte function may prove important to disease pathogenesis. Given the limited success of immunomodulatory therapies in treating inflammatory diseases, we propose that the immunologic function of RBCs provides an understudied and potentially rich area of research that may yield novel insights into mechanisms of immune regulation.

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