The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity H. Luke Anderson, Igor E. Brodsky and Nilam S. Mangalmurti This information is current as of September 27, 2021. J Immunol 2018; 201:1343-1351; ; doi: 10.4049/jimmunol.1800565 http://www.jimmunol.org/content/201/5/1343 Downloaded from References This article cites 102 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/201/5/1343.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity x { H. Luke Anderson,* Igor E. Brodsky,†,‡ and Nilam S. Mangalmurti‡, , The field of red cell biology is undergoing a quiet rev- mitophagy (2, 4). Loss of the erythroid nucleus is thought to have olution. Long assumed to be inert oxygen carriers, facilitated the evolution of mammalian endothermy, as it allowed RBCs are emerging as important modulators of the in- erythrocytes to further specialize for efficient gas exchange (4). nate immune response. Erythrocytes bind and scavenge In the classical literature, human erythrocytes have long been chemokines, nucleic acids, and pathogens in circulation. typecast as mere oxygen transporters. However, mounting evi- Depending on the conditions of the microenvironment, dence suggests that these cells also play an important role in the erythrocytes may either promote immune activation or innate immune system (5–7). From an evolutionary perspective, maintain immune quiescence. We examine erythrocyte the involvement of human erythrocytes in innate immunity Downloaded from immune function through a comparative and evolution- should not be surprising, as the nucleated erythrocytes of birds, ary lens, as this framework may offer perspective into amphibians, and fishes actively participate in the immune re- newly recognized roles of human RBCs. Next, we re- sponse via production of cytokine-like factors, upregulation of viral response genes, and sequestration of pathogens through view the known immune roles of human RBCs and surface binding or phagocytosis (8–20). Despite their deletion discuss their activity in the context of sepsis where of organelles during erythropoiesis and subsequent inability to http://www.jimmunol.org/ erythrocyte function may prove important to disease carry out transcription and translation, mammalian erythrocytes pathogenesis. Given the limited success of immuno- retain the ability to interact with endogenous and exogenous modulatory therapies in treating inflammatory diseases, inflammatory molecules in the blood. Research over the past we propose that the immunologic function of RBCs several decades demonstrates that, like their evolutionary provides an understudied and potentially rich area of counterparts, these cells retain the ability to bind and interact research that may yield novel insights into mechanisms with a variety of inflammatory molecules, including chemo- of immune regulation. The Journal of Immunology, kines, nucleic acids, and pathogens, thereby regulating and 2018, 201: 1343–1351. modulating immune responses. Internal components of eryth- by guest on September 27, 2021 rocytes such as hemoglobin and heme are also formidable facets of innate immunity, capable of generating antimicrobial reactive rythrocytes are the most abundant cell type in the oxygen species (ROS) to defend against invading hemolytic human body, numbering between 20 and 30 trillion microbes as well as promoting pathologic inflammatory and and accounting for nearly 70% of the total cell count in E autoimmune responses. Finally, the involvement of erythrocytes the average adult (1). Erythropoiesis begins with the differenti- in host–pathogen interactions may render them crucially im- ation of multipotent hematopoietic stem cells in the bone portant in the context of sepsis and septic shock, a state of marrow, which then give rise to erythroid-committed precursors. dysregulated host response to infection where the body is In the final stages of the process, known as terminal erythro- overwhelmed with endotoxins and other inflammatory media- poiesis, the nucleus and other organelles are extruded. These tors. A deeper understanding of erythrocyte function will likely enucleated reticulocytes are then released into the bloodstream to be vital to elucidating the ways in which these cells contribute to complete their maturation process (2). After a lifespan of ∼120 d, the pathogenesis of a variety of acute and chronic diseases. RBCs are cleared by macrophages in the spleen and liver (3). Importantly, mammals are the only vertebrates whose eryth- rocytes are enucleated in their mature state. The extrusion of Evolutionary perspectives the nucleus and other organelles occurs through a series of Erythrocyte origins. Throughout the course of evolution, the complex stages, including chromatin condensation, budding, and cellular components of the blood have undergone functional *Department of Biology, University of Pennsylvania, Philadelphia, PA 19104; Health Affairs through the Peer Reviewed Medical Research Program under Contract †Department of Pathobiology, University of Pennsylvania School of Veterinary Medi- W81XWH-15-1-0363 (to N.S.M.). cine, Philadelphia, PA 19104; ‡Institute for Immunology, Perelman School of Medicine, x Address correspondence and reprint requests to Dr. Nilam S. Mangalmurti, Perelman University of Pennsylvania, Philadelphia, PA 19104; Pulmonary, Allergy and Critical School of Medicine, University of Pennsylvania, 220 Stemmler Hall, 3450 Hamilton Care Division, Department of Medicine, Perelman School of Medicine, University of { Walk, Philadelphia, PA 19104. E-mail address: [email protected] Pennsylvania, Philadelphia, PA 19104; and Penn Center for Pulmonary Biology, Perel- man School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abbreviations used in this article: DAMP, damage-associated molecular pattern; DARC, Duffy Ag receptor for chemokines; GYPA, glycophorin A; HO-1, heme oxygenase-1; ORCIDs: 0000-0002-4150-0517 (H.L.A.); 0000-0001-7970-872X (I.E.B.); 0000- mtDNA, mitochondrial DNA; NRBC, nucleated RBC; ROS, reactive oxygen species. 0002-9146-1608 (N.S.M.). Received for publication April 20, 2018. Accepted for publication May 16, 2018. Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 This work was supported by National Institutes of Health Award HL126788 (to N.S.M.). This work was also supported by the Office of the Assistant Secretary of Defense for www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800565 1344 BRIEF REVIEWS: IMMUNOMODULATORY EFFECTS OF RBCs specialization. The earliest blood cells are thought to have been behavior was co-opted by the malarial parasite or that it is relative generalists involved in both phagocytosis and nutrient the maladaptive consequence of an evolutionarily conserved delivery. However, they did not serve a function in oxygen mechanism of pathogen sequestration. transport (21, 22). Prior to the emergence of circulatory systems, Mammalian erythrocytes. Mammals are the only vertebrates with small invertebrates accomplished tissue oxygenation by simple enucleated erythrocytes under homeostatic conditions (Fig. 1). diffusion alone; this mechanism is still observed today in prim- Intriguingly, however, nucleated erythrocytes are sometimes itive animals such as the sponges, cnidarians, and flatworms (21, observed in humans during pathologic states, constituting a 23). Later, the emergence of larger body plans necessitated more striking exception and suggesting that enucleated erythrocytes efficient oxygen delivery mechanisms, leading to the evolution of are not an obligate feature of mammalian physiology (32–34). increasingly elaborate circulatory systems (23) and a variety of Mammalian erythrocytes also lack endoplasmic reticula, ribo- oxygen-carrying respiratory pigments (24, 25). Hemoglobin somes, and mitochondria, as early developmental processes appears to have arisen first among them, followed by the expunge these typically vital organelles (2). It has been hypoth- hemerythrins, the molluscan hemocyanins, and eventually the esized that the deletion of nuclei and organelles in mature arthropod hemocyanins (25). Although hemoglobin likely erythrocytes may have allowed for increased surface area– began as a free-floating protein, the emergence of cells to to-volume ratio, facilitating increased gas exchange efficiency encapsulate the pigment (i.e., erythrocytes) appears to have (35–37). Moreover, the feature allowed for elevated cellular occurred soon after (24, 25). All modern vertebrates [with the hemoglobin capacity (4), increased pliability, and an improved