Background Mer receptor tyrosine kinase (MerTK) is key for efficient phagocytosis of apoptotic neutrophils (ANs) and homeostasis of IL-10 production by human anti-inflammatory M2c monocytes/macrophages. We asked whether stimulation of certain M2c surface receptors contribute in turn to MerTK activation.
Methods Human monocytes/macrophages were differentiated under M1, M2a and M2c polarizing conditions. We tested the effects of antibody-mediated cross-linking of M2c receptors (i.e., CD14, CD16, CD32, CD163, CD204) on MerTK phosphorylation and phagocytosis of ANs. MerTK expression was also studied by flow cytometry and western blot in the presence of LPS and in M2c-derived microvesicles (MVs).
Results Antibody cross-linking of either CD14 or CD32/FcγRII led to Syk activation and MerTK phosphorylation in its two distinct glycoforms (175–205 and 135–155 KDa). Cross-linked CD14 enhanced efferocytosis by M2c macrophages and enabled M1 and M2a cells to clear ANs efficiently. In M1 conditions, LPS abolished surface MerTK expression on CD14bright cell subsets, so disrupting the anti-inflammatory pathway. In M2c cells, instead, MerTK was diffusely and brightly co-expressed with CD14, and was also detected in M2c macrophage-derived MVs; in these conditions, LPS only partially down-regulated MerTK on the cell surface, while the smaller MerTK glycoform contained in MVs remained intact.
Conclusions Cooperation between CD14 and MerTK fosters tethering and engulfment of ANs by human monocytes/macrophages. CD14 stands between M1-related LPS co-receptor activity and M2c-related MerTK-dependent responses. MerTK interaction with CD32/FcγRII, its detection in M2c MVs, and the differential localization and LPS susceptibility of MerTK glycoforms add further new elements to the complexity of the MerTK network.
Acknowledgements NIAID and Lupus Research Alliance
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