Activated Platelets Convert CD14+CD16- Into CD14+CD16+ Monocytes With Enhanced FcγR-Mediated Phagocytosis and Skewed M2 Polarization

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.

Increase of Circulating Monocyte–Platelet Conjugates in Rheumatoid Arthritis Responders to IL-6 Blockage

“…These findings suggest that an inflammatory environment contributes to the binding of PLT to monocytes with a regulatory effect. Whereas, like other authors, we have not found any statistical association between PLT activation markers and disease activity [ 50 ], Lee et al found a correlation between sCD62P levels and disease activity, CRP and ESR [ 51 ]. This discrepancy between studies may be due to differences in cohort characteristics.…”

“…It is possible that IL-6 modifies the activation status of monocytes. Another possibility is that IL-6 induces CD16 expression on monocytes and PLTs would therefore preferentially bind to CD16+ monocytes [ 34 , 37 , 51 ]. This is unlikely in our settings because we did not find differences in CD16 expression on monocytes cultured for 28 h with or without rhIL-6 (data not shown).…”

Double-Spin Leukocyte-Rich Platelet-Rich Plasma Is Predominantly Lymphocyte Rich With Notable Concentrations of Other White Blood Cell Subtypes

“…35 Finally, a recent study by Lee et al demonstrated that activated platelets skewed monocyte differentiation to the M2 subset and can even convert some monocytes from M1 to M2. 36 Put together, it is clear that the monocytes found in PRP have the potential to significantly modulate the inflammatory environment at the site of local injection.…”

Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis, including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

“…Beyond their hemostatic activity, activated platelets trigger NET formation and modulate cellular functions of adjacent immune cells [48]. This study, among others, has provided evidence that activated platelets, as well as pEVs, induce a shift towards inflammatory CD16 + monocyte subsets [49][50][51], which has been implicated in disease severity in sepsis as well as in COVID-19 [52]. Furthermore, numerous studies have consistently demonstrated platelet hyperactivation in COVID-19 patients, especially in those with severe disease [2].…”