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-2- to 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 kappa B 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.