Platelet Mediated Monocyte/Macrophage Immune Training

Abstract Platelets are essential mediators of vascular and immune homeostasis as well as mediators of thrombosis. Platelet functions in hemostasis and thrombosis have received great attention in both basic and clinical research, however, emerging research indicates platelets are also critical components of the immune system. Platelets have important roles in many inflammation-associated diseases including sepsis, atherosclerosis, and peripheral artery disease. In recent years, much interest has focused on the acute outcomes of interactions between platelets and monocytes/macrophages in immune responses to bacterial infections, as several studies have demonstrated that platelets contribute to bacteria clearance and inflammation resolution by regulating monocyte/macrophage responses and their immune differentiation. However, macrophages are long-lived cells and past stimulation and immune interactions can change their responses to future stimuli - a concept termed 'innate immune memory'. Whether platelet interactions with monocytes/macrophages alters their inflammatory responses to secondary stimuli in a long-lasting manner remains unclear. We have now found that platelet interactions with monocytes and macrophages as a first stimulus, changed their responses to secondary stimuli, such as lipopolysaccharide (LPS) and unmethylated cytosine-phosphate-guanine (CpG). We incubated monocytes or macrophages with control buffer or platelets overnight and then removed the platelets prior to the addition of LPS or CpG as secondary stimulation. LPS and CpG induced IL-6 and TNFα were reduced by platelet pre-incubation compared to platelet naïve macrophages. Despite reduced cytokine secretion, platelet pre-incubation increased monocyte and macrophage proliferation in response to secondary stimuli. Furthermore, the platelet mediated macrophage secondary stimuli phenotype was preserved for several days after platelet exposure indicating a genetic reprogramming mediated mechanism. Circulating monocytes from platelet deficient TPOR -/- mice and adult mice made platelet deficient also had higher Il6 expression and secrete more IL-6 in response to stimulation compared to monocytes from WT mice indicating in vivo platelet mediated monocyte immune-training. Furthermore, the genetic reprogramming may be dependent on a HIF1α dependent process, as platelet pre-incubation increased macrophage Hif1α expression, a known mediator of trained immunity. Monocytes and macrophages, are 'immune plastic' and adapt to their environment in a functional manner. These novel data indicate that platelets 'reprogram' monocytes/macrophages and shape their responses to future stimulation. Disclosures No relevant conflicts of interest to declare.