Indian Journal of Infammation Research Page 1 of 2 IJIR. 2021;(5)1:WW1 Immune functon? Consult me too, RBCs’ authentc claim! 1 Associate Dean of Medical Research, SRM Medical College Hospital & Research Centre (SRMIST), Chennai, India It has been presumed for long that ferrying oxygen is the only function of red blood cells (RBCs) and the same has been taught in schools and through standard textbooks. However, a new research published in October this year by Lam et al. has revealed that RBCs play a much more signifcant role in the immune system and function through their DNA-binding capability, a newly discovered mechanism. 1 RBC functions beyond oxygen transport RBCs, variedly referred to as red cells/red blood corpuscles/hematids/erythroid cells or erythrocytes, are the most common abundant type of blood cells and the vertebrates’ principal means of delivering oxygen (O 2 ) to the body tissues via circulatory system. RBCs play a key role in the CO 2 transport and they ensure that most of the CO 2 is transported as bicarbonate. RBCs also perform various secondary functions. ATP release by RBCs, when they undergo shear stress in constricted vessels, has been shown to cause the vessel walls to relax and dilate to promote normal blood fow. 2 When the hemoglobin molecules are deoxygenated, RBCs release S-nitrosothiols, which also act to dilate blood vessels, thus directing more blood to areas of the body depleted of oxygen. 3 Like endothelial cells, RBCs can also synthesize nitric oxide enzymatically using L-arginine as substrate. 4 Exposure of RBCs to physiological levels of shear stress has been known to activate nitric oxide synthase and export of nitric oxide, which is linked to the regulation of vascular tone. 5 Interestingly, RBCs can also produce hydrogen sulfde, a gaseous signaling second messenger that acts to relax vessel walls. It is believed that the cardioprotective efects of garlic are due to RBCs that convert its sulfur compounds into hydrogen sulfde. 6 Revisiting red cell biology in the context of immune function Despite the assumption of their primary service as oxygen carriers, RBCs are now re-visited and emerging as important modulators of the innate immune response. The possibility that RBCs could participate in the defensive mechanism of the human body was postulated long ago by Bishlawy, as RBCs serve as both mechanical and biochemical barriers against infections, bacteria, and blood parasites. 7 Mounting evidence suggests that RBCs also play an important role in the innate immune system, as these cells, in an evolutionary perspective, have shown to retain the ability to bind and interact with a variety of infammatory molecules including chemokines, nucleic acids, and pathogens, thereby regulating and modulating immune responses. 8-10 As reviewed by Anderson et al., studying the evolutionary conservation of innate immunity role of RBCs in humans is a thrust area of research, as we already knew that the nucleated erythrocytes of birds, amphibians, and fshes actively participate in the immune response via production of cytokine-like factors, upregulation of viral response genes, and sequestration of pathogens through surface binding or phagocytosis. 11 In the above context, the recent work led by Mangalmurti and colleagues titled ‘DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia’, received greater attention as the fnding has clinical translation and utility. 1 Earlier, this group has pioneered and reported that human erythrocytes express TLR9 and found that TLR9-positive erythrocytes bind and sequester circulating cell-free mtDNA, and in vivo mouse studies demonstrated that loss of this function resulted in enhanced lung injury during states of infammation. 10 RBCs use TLR9 to scavenge cell-free mitochondrial DNA, which is present at low levels during normal cellular turnover and circulates at an increased level during illness or extensive cell death. It appears that depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. COVID-19 infection and RBCs’ confession COVID-19 research has unraveled novel new-biology Muthuswamy Balasubramanyam 1 * WHAT IS NEW? WHAT IS HOT?