MRP8/14 mediates macrophage efferocytosis through RAGE and Gas6/MFG‐E8, and induces polarization via TLR4‐dependent pathway

Abstract

Myeloid-related protein 8/14 (MRP8/14) participates in various inflammatory responses, however, its effect on macrophage efferocytosis remains unclear. Here, we demonstrate that MRP8/14 significantly inhibits the efferocytosis of apoptotic thymocytes by mouse bone marrow-derived macrophages (BMDMs), which later proves to be associated with the receptor for advanced glycation end products (RAGE) or for reducing the expression of growth arrest-specific protein 6 and milk fat globule epidermal growth factor 8, independent of RAGE. Furthermore, MRP8/14 promotes polarization of BMDMs from the M 2to M 1-like phenotype by upregulating expression of M 1-related surface receptor proteins and signature M 1-marker genes and by downregulating signature M 2-marker gene expression, which depends on Toll-like receptor 4 and p38 mitogen-activated protein kinase/nuclear factor κB pathways. Thus, we report a significant inhibitory effect of MRP8/14 on macrophage efferocytosis and MRP8/14-mediated phenotypic polarization, which may be helpful in developing novel therapeutic strategies leading to inflammation resolution. K E Y W O R D S efferocytosis, myeloid-related protein, polarization, receptor of advanced glycation end products, Toll-like receptor 4 1 | INTRODUCTION Efferocytosis refers to the engulfment and removal of apoptotic cells from inflammatory sites by macrophages, which is beneficial for resolving inflammation (Headland & Norling, 2015; Henson, 2017). During apoptosis, cellular phosphatidylserine (PtdSer) is flipped to the outer side of the membrane, allowing recognition and binding by macrophages either through PtdSer receptors such as receptors of advanced glycation end products (RAGE) or the assistance of bridging molecules such as growth arrest-specific protein 6 (Gas6) and milk fat globule epidermal growth factor 8 (MFG-E8; Greenlee-Wacker, 2016; Ravichandran, 2010). Gas6 links PtdSer to the protooncogene Mer tyrosine kinase (MerTK) on macrophages, and MFG-E8 bridges externalized PtdSer and α v β 3 integrin (Elliott, Koster, & Murphy, 2017; Gilroy & De Maeyer, 2015). In addition, efferocytosis can be triggered by various inflammatory mediators, such as lipopolysaccharide (LPS; Feng et al., 2011) and high-mobility group box 1

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