Red blood cells: the immune system’s hidden regulator, investigation into the role of red blood cells in inflammatory cytokine signalling

Abstract

Red blood cells are the most abundant cell type in mammals, although, they are mostly described as inert carriers of haemoglobin that function only in gas exchange and transport. Evidence is now mounting that these enucleate cells are more complex than previously understood. Studies have reported that red blood cells from healthy individuals regulate immune cell activity and maturation, but red blood cells from inflammatory disease cohorts are dysfunctional. Red blood cells are known to bind a small number of chemokines and have been described as a sink for these molecules, and the loss of this activity is correlated with disease progression. This results of this thesis support a broader role for red blood cells in regulating inflammation by acting as a cytokine buffer and modulating cell activity. The aims and hypotheses of this thesis were founded on the discovery that red blood cells are a major reservoir for the pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF); in fact, they contribute 1000-fold more per millilitre than plasma. Red blood cells were also identified to be a major reservoir of 30 additional cytokines, chemokines, and growth factors. Further investigation showed that red blood cells bind and release significant quantities of these proteins, a function that can be modulated by other cells and by enzyme inhibitors. Incubating red blood cells with a cancer cell line (A549 cells) resulted in the significant increase of eight pro-tumorigenic cytokines in the red blood cell lysates. These primed red blood cells altered the activity of lymphocytes by stimulating the proliferation of T cells compared to controls, and promoted the expression of cell activation markers. This study supports the hypothesis that red blood cells act as a buffer for cytokines through binding and release, and that alterations in red blood cells from cell-to-cell interactions affects the activity of T cells. This thesis proposes that red blood cells have multiple functions and the results have implications for the study of inflammation, the role of red blood cells in diagnostics, and on the development of red blood cell derived therapeutics.