TY - JOUR
T1 - Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells
AU - Wang, Ying
AU - Cao, Ying
AU - Mangalam, Ashutosh K.
AU - Guo, Yong
AU - LaFrance-Corey, Reghann G.
AU - Gamez, Jeffrey D.
AU - Atanga, Pascal Aliihnui
AU - Clarkson, Benjamin D.
AU - Zhang, Yuebo
AU - Wang, Enfeng
AU - Angom, Ramcharan Singh
AU - Dutta, Kirthica
AU - Ji, Baoan
AU - Pirko, Istvan
AU - Lucchinetti, Claudia F.
AU - Howe, Charles L.
AU - Mukhopadhyay, Debabrata
N1 - Publisher Copyright:
© 2016. Published by The Company of Biologists Ltd.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Brain microvascular endothelial cells
KW - Inflammatory response
KW - Interferon-γ
KW - Neuroinflammatory diseases
KW - Neuropilin-1
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U2 - 10.1242/jcs.190702
DO - 10.1242/jcs.190702
M3 - Article
C2 - 27591257
AN - SCOPUS:84995503979
SN - 0021-9533
VL - 129
SP - 3911
EP - 3921
JO - Journal of cell science
JF - Journal of cell science
IS - 20
ER -