Essential role of DAP12 signaling in macrophage programming into a fusion-competent state

Sci Signal. 2008 Oct 28;1(43):ra11. doi: 10.1126/scisignal.1159665.

Abstract

Multinucleated giant cells, formed by fusion of macrophages, are a hallmark of granulomatous inflammation. With a genetic approach, we show that signaling through the adaptor protein DAP12 (DNAX activating protein of 12 kD), its associated receptor triggering receptor expressed by myeloid cells 2 (TREM-2), and the downstream protein tyrosine kinase Syk is required for the cytokine-induced formation of giant cells and that overexpression of DAP12 potentiates macrophage fusion. We also present evidence that DAP12 is a general macrophage fusion regulator and is involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DC-STAMP and Cadherin 1. Thus, DAP12 is involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Cell Fusion*
  • Cytokines / pharmacology
  • Gene Expression Regulation
  • Inflammation / pathology
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Macrophages / pathology*
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Protein-Tyrosine Kinases / physiology*
  • Receptors, Immunologic / physiology*
  • Signal Transduction / genetics*
  • Syk Kinase

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Tyrobp protein, mouse
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse