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

Ying Wang, Ying Cao, Ashutosh K. Mangalam, Yong Guo, Reghann G. LaFrance-Corey, Jeffrey D. Gamez, Pascal Aliihnui Atanga, Benjamin D. Clarkson, Yuebo Zhang, Enfeng Wang, Ramcharan Singh Angom, Kirthica Dutta, Baoan D Ji, Istvan Pirko, Claudia F Lucchinetti, Charles L Howe, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

8 Scopus citations

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, themolecularmechanismmediating 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-Cmotif 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.

Original languageEnglish (US)
Pages (from-to)3911-3921
Number of pages11
JournalJournal of Cell Science
Volume129
Issue number20
DOIs
StatePublished - 2016

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Keywords

  • Brain microvascular endothelial cells
  • Inflammatory response
  • Interferon-γ
  • Neuroinflammatory diseases
  • Neuropilin-1

ASJC Scopus subject areas

  • Cell Biology

Cite this

Wang, Y., Cao, Y., Mangalam, A. K., Guo, Y., LaFrance-Corey, R. G., Gamez, J. D., Atanga, P. A., Clarkson, B. D., Zhang, Y., Wang, E., Angom, R. S., Dutta, K., Ji, B. D., Pirko, I., Lucchinetti, C. F., Howe, C. L., & Mukhopadhyay, D. (2016). Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells. Journal of Cell Science, 129(20), 3911-3921. https://doi.org/10.1242/jcs.190702