Activated platelet-mediated induction of CD16 expression and its role in human monocytes

Abstract

Abstract Monocytes are important cellular effectors of innate immune defense. In humans, circulating monocytes are heterogeneous and can be divided into three distinct subsets based on CD14 and CD16 expression. The expansion of “intermediate” CD14+CD16+ monocytes is well reported in many chronic inflammatory conditions such as rheumatoid arthritis (RA). However, the mechanism underlying induction of CD16 and the role of CD16 in CD14+CD16+ monocytes remain unclear. ADP-treated autologous platelets induced CD16 expression by highly purified “conventional” CD14+CD16− monocytes. Given that platelet activation causes the release of several soluble factors, we examined an effect of cytokines, which are involved in monocyte-platelet aggregation (MPA), on CD16 induction. MPA led to significantly increased production of TGF-β and IL-6. Exogenous TGF-β and IL-6 in platelet-free culture induced CD16 expression, whereas neutralizing antibodies for TGF-β and IL-6 largely suppressed CD16 induction. Furthermore, selective inhibitors of SMAD3 and STAT3 reduced CD16 expression, indicating a critical role of TGF-β and IL-6 for CD16 induction by CD14+CD16− monocytes. Functionally, induced CD16 participates in IgG-mediated phagocytosis and the level of CD16 expression in activated platelet-treated monocytes is correlated with uptake of beads coated with FITC-labeled IgG. Lastly, CD14+CD16− monocytes treated with activated platelets differentiate into M2-like macrophage. Our findings suggest an important role of activated platelets for modulating phenotypical and functional features of monocytes in humans. This will be helpful for understanding immunological role of CD14+CD16+ in chronic inflammatory diseases.