Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation

Hum Mol Genet. 2016 Mar 15;25(6):1129-39. doi: 10.1093/hmg/ddv635. Epub 2016 Jan 5.

Abstract

Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carotid Arteries / metabolism
  • Carotid Arteries / pathology
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Genes, Neurofibromatosis 1
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / metabolism
  • Monocytes / pathology*
  • Myocytes, Smooth Muscle / metabolism
  • Neointima / genetics
  • Neointima / metabolism
  • Neointima / pathology*
  • Neurofibromatosis 1 / genetics
  • Neurofibromatosis 1 / metabolism
  • Neurofibromatosis 1 / pathology*
  • Neurofibromin 1 / genetics
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*
  • Signal Transduction

Substances

  • Ccr2 protein, mouse
  • Chemokine CCL2
  • Neurofibromin 1
  • Receptors, CCR2