Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells

J Cell Sci. 2016 Oct 15;129(20):3911-3921. doi: 10.1242/jcs.190702. Epub 2016 Sep 2.

Abstract

Inflammatory response of blood-brain barrier (BBB) endothelial cells plays an important role in pathogenesis of many central nervous system inflammatory diseases, including multiple sclerosis; however, the molecular mechanism mediating BBB endothelial cell inflammatory response remains unclear. In this study, we first observed that knockdown of neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, suppressed interferon-γ (IFNγ)-induced C-X-C motif chemokine 10 expression and activation of STAT1 in brain microvascular endothelial cells in a Rac1-dependent manner. Moreover, endothelial-specific NRP1-knockout mice, VECadherin-Cre-ERT2/NRP1flox/flox mice, showed attenuated disease progression during experimental autoimmune encephalomyelitis, a mouse neuroinflammatory disease model. Detailed analysis utilizing histological staining, quantitative PCR, flow cytometry and magnetic resonance imaging demonstrated that deletion of endothelial NRP1 suppressed neuron demyelination, altered lymphocyte infiltration, preserved BBB function and decreased activation of the STAT1-CXCL10 pathway. Furthermore, increased expression of NRP1 was observed in endothelial cells of acute multiple sclerosis lesions. Our data identify a new molecular mechanism of brain microvascular endothelial inflammatory response through NRP1-IFNγ crosstalk that could be a potential target for intervention of endothelial cell dysfunction in neuroinflammatory diseases.

Keywords: Brain microvascular endothelial cells; Inflammatory response; Interferon-γ; Neuroinflammatory diseases; Neuropilin-1.

Publication types

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

MeSH terms

  • Animals
  • Blood-Brain Barrier / pathology
  • Brain / blood supply*
  • Chemokine CXCL10
  • Disease Models, Animal
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Deletion
  • Gene Knockdown Techniques
  • Humans
  • Inflammation / pathology
  • Interferon-gamma / pharmacology*
  • Mice, Inbred C57BL
  • Microvessels / cytology*
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Neuropilin-1 / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Up-Regulation / drug effects
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Chemokine CXCL10
  • STAT1 Transcription Factor
  • Neuropilin-1
  • Interferon-gamma
  • rac1 GTP-Binding Protein