Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Justin E. Lengfeld; Sarah E. Lutz; Julian R. Smith; Claudiu Diaconu; Cameron Scott; Sigal B. Kofman; Claire Choi; Craig M. Walsh; Cedric S. Raine; Ilir Agalliu; Dritan Agalliu

doi:10.1073/pnas.1609905114

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Justin E. Lengfeld, Sarah E. Lutz, Julian R. Smith, Claudiu Diaconu, Cameron Scott, Sigal B. Kofman, Claire Choi, Craig M. Walsh, Cedric S. Raine, Ilir Agalliu, Dritan Agalliu

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4⁺ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.

Original language	English (US)
Pages (from-to)	E1168-E1177
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1609905114
State	Published - Feb 14 2017
Externally published	Yes

Bibliographical note

Funding Information:
J.E.L., S.E.L., J.R.S., and D.A. were supported by funding from the NIH National Heart, Lung, and Blood Institute (Grant R01 HL116995-01), the National Institute of Mental Health (Grant R56 MH109987-01A1), the National Multiple Sclerosis Society (Grant RG4673A1/1), and the Leducq Foundation. S.E.L. received a fellowship from the National Multiple Sclerosis Society (Award FG2035-A-1). D.A. is partially supported by an unrestricted gift from John. F. Castle to the Division of Stroke, Department of Neurology at Columbia University Medical Center. C.D. was supported by funding from the NIH National Institute of Neurological Disorders and Stroke (Grant R25 NS070697). C.M.W. is supported by funding from the California Institute for Regenerative Medicine (Grant TR3-05603) and the National Multiple Sclerosis Society (Grant CA 1058-A-8). C.S.R. was a Wollowick Professor at Albert Einstein and was supported by the National Multiple Sclerosis Society (Grant RG1001-K11). The confocal facility in the Optical Biology Shared Resource at the University of California, Irvine was funded by National Institutes of Health Cancer Center Support Grant CA-62203.

Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.

Keywords

Blood-brain barrier
EAE
Endothelial cell
MS
Wnt/β-catenin signaling

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1073/pnas.1609905114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320985

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Lengfeld, J. E., Lutz, S. E., Smith, J. R., Diaconu, C., Scott, C., Kofman, S. B., Choi, C., Walsh, C. M., Raine, C. S., Agalliu, I., & Agalliu, D. (2017). Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 114(7), E1168-E1177. https://doi.org/10.1073/pnas.1609905114

Lengfeld, JE, Lutz, SE, Smith, JR, Diaconu, C, Scott, C, Kofman, SB, Choi, C, Walsh, CM, Raine, CS, Agalliu, I & Agalliu, D 2017, 'Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 7, pp. E1168-E1177. https://doi.org/10.1073/pnas.1609905114

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abstract = "Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.",

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author = "Lengfeld, {Justin E.} and Lutz, {Sarah E.} and Smith, {Julian R.} and Claudiu Diaconu and Cameron Scott and Kofman, {Sigal B.} and Claire Choi and Walsh, {Craig M.} and Raine, {Cedric S.} and Ilir Agalliu and Dritan Agalliu",

note = "Funding Information: J.E.L., S.E.L., J.R.S., and D.A. were supported by funding from the NIH National Heart, Lung, and Blood Institute (Grant R01 HL116995-01), the National Institute of Mental Health (Grant R56 MH109987-01A1), the National Multiple Sclerosis Society (Grant RG4673A1/1), and the Leducq Foundation. S.E.L. received a fellowship from the National Multiple Sclerosis Society (Award FG2035-A-1). D.A. is partially supported by an unrestricted gift from John. F. Castle to the Division of Stroke, Department of Neurology at Columbia University Medical Center. C.D. was supported by funding from the NIH National Institute of Neurological Disorders and Stroke (Grant R25 NS070697). C.M.W. is supported by funding from the California Institute for Regenerative Medicine (Grant TR3-05603) and the National Multiple Sclerosis Society (Grant CA 1058-A-8). C.S.R. was a Wollowick Professor at Albert Einstein and was supported by the National Multiple Sclerosis Society (Grant RG1001-K11). The confocal facility in the Optical Biology Shared Resource at the University of California, Irvine was funded by National Institutes of Health Cancer Center Support Grant CA-62203. Publisher Copyright: {\textcopyright} 2017, National Academy of Sciences. All rights reserved.",

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AU - Lutz, Sarah E.

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AU - Scott, Cameron

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AU - Walsh, Craig M.

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AU - Agalliu, Ilir

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N2 - Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.

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Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Abstract

Bibliographical note

Keywords

UN SDGs

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