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

Waylan K. Bessler, Grace Kim, Farlyn Z. Hudson, Julie A. Mund, Raghuveer Mali, Keshav Menon, Reuben Kapur, D. Wade Clapp, David A. Ingram, Brian K. Stansfield

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 p21Ras, 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.

Original languageEnglish (US)
Pages (from-to)1129-1139
Number of pages11
JournalHuman molecular genetics
Volume25
Issue number6
DOIs
StatePublished - Aug 17 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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