Abstract
Monocytes are important cellular effectors of innate immune defense. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. The expansion of intermediate CD14+CD16+ monocytes has been reported in chronic inflammatory diseases including rheumatoid arthritis (RA). However, the mechanism underlying induction of CD16 and its role in monocytes remains poorly understood. Here, we demonstrate that activated platelets are important for induction of CD16 on classical CD14+CD16- monocytes by soluble factors such as cytokines. Cytokine neutralization and signaling inhibition assays reveal that sequential involvement of platelet-derived TGF-β and monocyte-derived IL-6 contribute to CD16 induction on CD14+CD16- monocytes. Activated platelet-induced CD16 on monocytes participates in antibody-dependent cellular phagocytosis (ADCP) and its level is positively correlated with phagocytic activity. CD14+CD16- monocytes treated with activated platelets preferentially differentiate into M2 macrophages, likely the M2c subset expressing CD163 and MerTK. Lastly, the amount of sCD62P, a marker of activated platelets, is significantly elevated in plasma of RA patients and positively correlates with clinical parameters of RA. Our findings suggest an important role of activated platelets in modulating phenotypical and functional features of human monocytes. This knowledge increases understanding of the immunological role of CD14+CD16+ cells in chronic inflammatory diseases.
Highlights
Monocytes are circulating blood leukocytes typically regarded as systemic precursors of macrophages and dendritic cells (DCs) [1,2,3]
The expansion of CD14+CD16+ monocytes has been reported in a variety of inflammatory disorders including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [11, 12, 31], implying an important role of these cells in disease pathogenesis
Considering that platelets are a major reservoir of TGF-b, we first tested whether platelets induce CD16 expression on human monocytes
Summary
Monocytes are circulating blood leukocytes typically regarded as systemic precursors of macrophages and dendritic cells (DCs) [1,2,3] Besides their primary role as precursors, monocytes act as important innate effectors in the pathogenesis of various inflammatory diseases as well as in the inflammatory response against infectious pathogens through phagocytosis, production of reactive oxygen species (ROS), secretion of proinflammatory soluble factors, and the activation of adaptive immunity [4, 5]. Peripheral monocytes are heterogeneous and classified into three functionally distinct subsets depending on the expression of CD14, a coreceptor for LPS, and CD16 ( known as FcgRIII). These include classical CD14+CD16-, intermediate CD14+CD16+, and nonclassical CD14dimCD16+ monocytes [6,7,8,9]. The mechanisms underlying the induction of CD16 are not fully understood
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