title: Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells.
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/floxmice, 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.
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Ying
authors: Y
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Ying
authors: 0000-0002-1392-4443
authors: Y
authors: Cao
authors: Department of Pathology, University of Iowa Carver College of Medicine, Iowa city, IA 52242, USA.
authors: Ashutosh K
authors: AK
authors: Mangalam
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Yong
authors: Y
authors: Guo
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Reghann G
authors: RG
authors: LaFrance-Corey
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Jeffrey D
authors: JD
authors: Gamez
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Pascal Aliihnui
authors: PA
authors: Atanga
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Benjamin D
authors: BD
authors: Clarkson
authors: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Yuebo
authors: Y
authors: Zhang
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Enfeng
authors: E
authors: Wang
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Ramcharan Singh
authors: RS
authors: Angom
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Kirthica
authors: 0000-0003-2815-7758
authors: K
authors: Dutta
authors: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Baoan
authors: B
authors: Ji
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Istvan
authors: I
authors: Pirko
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Claudia F
authors: CF
authors: Lucchinetti
authors: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Charles L
authors: CL
authors: Howe
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA mukhopadhyay.debabrata@mayo.edu.
authors: Debabrata
authors: 0000-0003-1858-5054
authors: D
authors: Mukhopadhyay
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology; D001921:Brain / Q000098:blood supply*; D054357:Chemokine CXCL10; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology*; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D039942:Neuropilin-1 / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D050794:STAT1 Transcription Factor; D039942:Neuropilin-1; D007371:Interferon-gamma; D020830:rac1 GTP-Binding Protein
keywords: Brain microvascular endothelial cells; Inflammatory response; Interferon-γ; Neuroinflammatory diseases; Neuropilin-1