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

J Cell Physiol. 2021 Feb;236(2):1375-1390. doi: 10.1002/jcp.29944. Epub 2020 Jul 20.

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 M2 - to M1 -like phenotype by upregulating expression of M1 -related surface receptor proteins and signature M1 -marker genes and by downregulating signature M2 -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.

Keywords: Toll-like receptor 4; efferocytosis; myeloid-related protein; polarization; receptor of advanced glycation end products.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / genetics*
  • Apoptosis / genetics
  • Calgranulin A / genetics*
  • Cell Polarity / genetics
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Milk Proteins / genetics*
  • NF-kappa B / genetics
  • Phagocytosis / genetics
  • Receptor for Advanced Glycation End Products / genetics
  • Signal Transduction
  • Thymocytes / metabolism
  • Thymocytes / pathology
  • Toll-Like Receptor 4 / genetics*
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Ager protein, mouse
  • Antigens, Surface
  • Calgranulin A
  • Intercellular Signaling Peptides and Proteins
  • Mfge8 protein, mouse
  • Milk Proteins
  • NF-kappa B
  • Receptor for Advanced Glycation End Products
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • growth arrest-specific protein 6
  • p38 Mitogen-Activated Protein Kinases