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 Ji; Istvan Pirko; Claudia F Lucchinetti; Charles L Howe; Debabrata Mukhopadhyay

doi:10.1242/jcs.190702

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

Journal article

Open access

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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, …

Journal of cell science, Vol.129(20), pp.3911-3921

10/15/2016

DOI: 10.1242/jcs.190702

PMCID: PMC5087664

PMID: 27591257

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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/NRP1 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.

Microvessels - cytology

Inflammation - pathology

Encephalomyelitis, Autoimmune, Experimental - pathology

Endothelial Cells - metabolism

Neuropilin-1 - metabolism

Humans

Mice, Inbred C57BL

Disease Progression

Chemokine CXCL10

Gene Knockdown Techniques

Up-Regulation - drug effects

Blood-Brain Barrier - pathology

Brain - blood supply

STAT1 Transcription Factor - metabolism

Animals

Signal Transduction - drug effects

Gene Deletion

Multiple Sclerosis - pathology

Interferon-gamma - pharmacology

rac1 GTP-Binding Protein - metabolism

Disease Models, Animal

Endothelial Cells - drug effects

Multiple Sclerosis - metabolism

Details

Title: Subtitle: Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells
Creators: Ying Wang - Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Ying Cao - Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Ashutosh K Mangalam - Department of Pathology, University of Iowa Carver College of Medicine, Iowa city, IA 52242, USA
Yong Guo - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Reghann G LaFrance-Corey - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Jeffrey D Gamez - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Pascal Aliihnui Atanga - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Benjamin D Clarkson - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Yuebo Zhang - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Enfeng Wang - Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Ramcharan Singh Angom - Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Kirthica Dutta - Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Baoan Ji - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
Istvan Pirko - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Claudia F Lucchinetti - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Charles L Howe - Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Debabrata Mukhopadhyay - Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA mukhopadhyay.debabrata@mayo.edu
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.129(20), pp.3911-3921
DOI: 10.1242/jcs.190702
PMID: 27591257
PMCID: PMC5087664
NLM abbreviation: J Cell Sci
ISSN: 0021-9533
eISSN: 1477-9137
Publisher: England
Grant note: R29 CA078383 / NCI NIH HHS R01 CA078383 / NCI NIH HHS R01 HL070567 / NHLBI NIH HHS AHA_14POST20390029 / American Heart Association-American Stroke Association UL1 TR000135 / NCATS NIH HHS K12 CA090628 / NCI NIH HHS
Language: English
Date published: 10/15/2016
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9984070726002771

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