Anucleated red blood cells (RBCs) are essential for delivery of oxygen throughout the body but have been considered immunologically inert. New evidence recently published in Science Translational Medicine, however, suggests that RBCs promote immune activation by binding to unmethylated, cell free CpG nucleic acid fragments and promoting cytokine production. Toll-like receptors play a key role in inflammation by identifying nucleic acid fragments. Lam and colleagues show that mammalian RBCs express the toll-like receptor 9 (TLR9) on their surface and that TLR9 surface expression is increased during sepsis. Furthermore, TLR9 expressed on RBCs binds pathogenic CpG nucleic acids resulting in altered RBC cytoskeletal proteins and Band 3 distribution. Lam et al also show that CpG binding by RBCs leads to attenuation of the RBC self-preservation marker CD47, resulting in accelerated erythrophagocytosis and activation of the innate immune system (by increased expression of interferon and interlukin-6). Consistent with these laboratory findings, they show that patients with severe and/or anemic COVID-19 have increased levels of nucleic acids bound to RBCs compared to patients with less severe disease. Further comprehensive studies are required to better understand how RBCs modulate innate inflammatory responses.
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