Red Blood Cells as Immune Guardians: Emerging Roles in Host Defense and Emergency Medicine

Red blood cells (RBCs), traditionally regarded as passive oxygen carriers, are now recognized as highly dynamic regulators of immune and vascular homeostasis, shaping host defence and inflammatory regulation. Their unique biophysical properties — including biconcave geometry, exceptional deformability, and uninterrupted circulation through virtually all tissues — position RBCs as sentinels constantly surveying the internal environment. Originating from a tightly regulated erythropoietic process, RBCs traverse the vascular system more than a thousand times per day, interacting with endothelial cells, platelets, plasma proteins, and innate and adaptive immune cells. While their classical function in oxygen and carbon dioxide transport remains fundamental, this role now appears to be only one dimension of a broader biological identity grounded in immunometabolic and mechano-immune regulation.Recent discoveries reveal that RBCs participate actively in pathogen surveillance, immune signaling, and inflammatory modulation. They bind and neutralize circulating danger-associated molecular patterns, including cell-free DNA and mitochondrial DNA via Toll-like receptors such as TLR9, and scavenge cytokines, toxins, and immune complexes, thereby influencing immune clearance pathways and erythrophagocytosis. RBC membrane signals, including the regulation of CD47 "don’t eat me" cues, contribute to fine-tuning inflammation and determining the balance between tolerance and immune activation. Furthermore, RBCs modulate complement activation, buffer oxidative stress, and release extracellular vesicles able to transfer bioactive molecules to immune and endothelial cells. Disruption of these processes, through hemolysis, oxidative injury, or altered deformability, is increasingly recognized as a central mechanism in sepsis, trauma-associated inflammatory responses, hemorrhagic shock, severe infections, ischemia–reperfusion injury, and inflammatory anemia.This new understanding converges with pivotal advances in emergency and critical-care medicine. A rapidly evolving field aims to harness RBC biology to develop innovative therapeutic platforms capable of delivering oxygen, controlling inflammation, and restoring tissue perfusion in acute care settings. The development of lyophilized RBC preparations illustrates this translational shift, enabling long-shelf-life, portable blood-based resuscitation products suitable for ambulances, pre-hospital interventions, combat environments, remote areas, and disaster medicine. In parallel, hemoglobin-based oxygen carriers have re-emerged as promising alternatives, notably the extracellular hemoglobin M101 derived from the marine annelid Arenicola marina. This molecule, which lacks ABO and Rh antigens, displays extraordinary oxygen-binding dynamics, nanometric diffusion capacity that supports microvascular oxygenation, and intrinsic antioxidant properties, suggesting broad utility in hemorrhagic shock, sepsis, carbon monoxide poisoning, and acute hypoxic states.Together, these advances define the contours of a new discipline at the intersection of immunology, hematology, vascular biology, and emergency medicine. The objective of this Research Topic is to consolidate these emerging insights, bridging fundamental erythro-immunology with cutting-edge translational and clinical strategies. We seek contributions that elucidate the immunological functions of RBCs, clarify their role in acute inflammatory and hypoxic syndromes, and explore innovative erythro-based therapeutic approaches — from engineered RBCs and extracellular vesicles to universal oxygen carriers and “immuno-oxygen” interventions. Through this effort, we aim to stimulate interdisciplinary dialogue and accelerate the transformation of a classical physiological cell into a central player in the therapeutic landscape of critical illness and acute care.This Research Topic brings together immunologists, hematologists, vascular biologists, emergency physicians, intensivists, bioengineers, and transfusion specialists to define the future of erythrocyte-based strategies and translate a classical cell into a cornerstone of next-generation immune-oxygen therapy, particularly in contexts of inflammation, sepsis, and acute care medicine.Manuscripts dealing with RBC metabolism and disease that do not focus on immunological aspects are out of scope for Frontiers in Immunology Topic editors: Mourad Aribi, Said Dermime, Xin Li Source: https://www.frontiersin.org/research-topics/77606/red-blood-cells-as-immune-guardians-emerging-roles-in-host-defense-and-emergency-medicine