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

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 - to M -like phenotype by upregulating expression of M -related surface receptor proteins and signature M -marker genes and by downregulating signature M -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.