ADGRE1 (EMR1, F4/80) Is a Rapidly-Evolving Gene Expressed in Mammalian Monocyte-Macrophages

Front Immunol. 2018 Oct 1;9:2246. doi: 10.3389/fimmu.2018.02246. eCollection 2018.


The F4/80 antigen, encoded by the Adgre1 locus, has been widely-used as a monocyte-macrophage marker in mice, but its value as a macrophage marker in other species is unclear, and has even been questioned. ADGRE1 is a seven transmembrane G protein-coupled receptor with an extracellular domain containing repeated Epidermal Growth Factor (EGF)-like calcium binding domains. Using a new monoclonal antibody, we demonstrated that ADGRE1 is a myeloid differentiation marker in pigs, absent from progenitors in bone marrow, highly-expressed in mature granulocytes, monocytes, and tissue macrophages and induced by macrophage colony-stimulating factor (CSF1) treatment in vivo. Based upon these observations, we utilized RNA-Seq to assess the expression of ADGRE1 mRNA in bone marrow or monocyte-derived macrophages (MDM) and alveolar macrophages from 8 mammalian species including pig, human, rat, sheep, goat, cow, water buffalo, and horse. ADGRE1 mRNA was expressed by macrophages in each species, with inter-species variation both in expression level and response to lipopolysaccharide (LPS) stimulation. Analysis of the RNA-Seq data also revealed additional exons in several species compared to current Ensembl annotations. The ruminant species and horses appear to encode a complete duplication of the 7 EGF-like domains. In every species, Sashimi plots revealed evidence of exon skipping of the EGF-like domains, which are highly-variable between species and polymorphic in humans. Consistent with these expression patterns, key elements of the promoter and a putative enhancer are also conserved across all species. The rapid evolution of this molecule and related ADGRE family members suggests immune selection and a role in pathogen recognition.

Keywords: ADGRE1/EMR1; F4/80; adhesion G protein-coupled receptor E1; bone marrow; macrophage; monocyte; porcine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, Differentiation / genetics*
  • Antigens, Differentiation / immunology
  • Base Sequence
  • Biomarkers
  • Bone Marrow Cells / cytology
  • Calcium-Binding Proteins
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Epidermal Growth Factor / genetics
  • Exons
  • Female
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Macrophages / physiology*
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mucins / genetics*
  • Mucins / immunology
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / immunology
  • Sus scrofa / genetics*
  • Transcription, Genetic


  • ADGRE1 protein, human
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, Differentiation
  • Biomarkers
  • Calcium-Binding Proteins
  • Membrane Glycoproteins
  • Mucins
  • Receptors, G-Protein-Coupled
  • monocyte-macrophage differentiation antigen
  • seven-transmembrane G-protein-coupled receptor
  • Epidermal Growth Factor