Vitamin D3-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D3 synthesis and correlates with increased CD4+ T cell CTLA-4 expression

Justin A. Spanier; Faye E. Nashold; Corwin D. Nelson; Corinne E. Praska; Colleen E. Hayes

doi:10.1016/j.jneuroim.2019.577105

Vitamin D₃-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D₃ synthesis and correlates with increased CD4⁺ T cell CTLA-4 expression

Justin A. Spanier, Faye E. Nashold, Corwin D. Nelson, Corinne E. Praska, Colleen E. Hayes

Medicine - Rheumatic and Autoimmune

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

21 Scopus citations

Abstract

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)₂D₃ synthesis on vitamin D₃-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)₂D₃ synthesis was essential for vitamin D₃-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4⁺ Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D₃ reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)₂D₃ production and CTLA-4 upregulation in CNS-infiltrating CD4⁺ T cells. We suggest that CTLA-4 serves as a vitamin D₃-regulated immunological checkpoint in multiple sclerosis prevention.

Original language	English (US)
Article number	577105
Journal	Journal of Neuroimmunology
Volume	338
DOIs	https://doi.org/10.1016/j.jneuroim.2019.577105
State	Published - Jan 15 2020

Bibliographical note

Funding Information:
We extend our gratitude to Dr. René St-Arnaud (Research Center, Shriners Hospital for Children, Canada, Montréal H4A A09) for the generous gift of C57BL/6 mice with loxP sites flanking exon 8 of the Cyp27b1 gene, to Dr. Shane Hubler for his guidance on statistical analyses, and to Dr. Brigitte Huber for her thoughtful review of the manuscript prior to submission. We also thank Ms. Dagna Sheerar for her valuable assistance with the flow cytometery experiments and Ms. Heather Suchomel for her conscientious animal care services. We acknowledge the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520 , United States, for supporting the Flow Cytometry Laboratory where some of the flow data was collected. We also acknowledge the Center for Autoimmune Disease Research at the University of Minnesota , United States ( UMF0020624 to J.A.S.), and a bridge funding award from the University of Wisconsin Department of Biochemistry , United States, to support the mouse colony. We are especially grateful to Thomas Wolfe and Patricia Powers for establishing the “Multiple Sclerosis Research Fund in Biochemistry” at the University of Wisconsin Foundation. Without their generosity, this research could not have been performed. Appendix A

Publisher Copyright:
© 2019 Elsevier B.V.

Keywords

Autoimmunity
Cyp27b1
EAE/MS
Gene targeting
Myeloid cells
Vitamin D

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Vitamin D₃-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D₃ synthesis and correlates with increased CD4⁺ T cell CTLA-4 expression. / Spanier, Justin A.; Nashold, Faye E.; Nelson, Corwin D. et al.
In: Journal of Neuroimmunology, Vol. 338, 577105, 15.01.2020.

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

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title = "Vitamin D3-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D3 synthesis and correlates with increased CD4+ T cell CTLA-4 expression",

abstract = "Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)2D3 synthesis on vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)2D3 synthesis was essential for vitamin D3-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4+ Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D3 reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)2D3 production and CTLA-4 upregulation in CNS-infiltrating CD4+ T cells. We suggest that CTLA-4 serves as a vitamin D3-regulated immunological checkpoint in multiple sclerosis prevention.",

keywords = "Autoimmunity, Cyp27b1, EAE/MS, Gene targeting, Myeloid cells, Vitamin D",

author = "Spanier, {Justin A.} and Nashold, {Faye E.} and Nelson, {Corwin D.} and Praska, {Corinne E.} and Hayes, {Colleen E.}",

note = "Funding Information: We extend our gratitude to Dr. Ren{\'e} St-Arnaud (Research Center, Shriners Hospital for Children, Canada, Montr{\'e}al H4A A09) for the generous gift of C57BL/6 mice with loxP sites flanking exon 8 of the Cyp27b1 gene, to Dr. Shane Hubler for his guidance on statistical analyses, and to Dr. Brigitte Huber for her thoughtful review of the manuscript prior to submission. We also thank Ms. Dagna Sheerar for her valuable assistance with the flow cytometery experiments and Ms. Heather Suchomel for her conscientious animal care services. We acknowledge the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520 , United States, for supporting the Flow Cytometry Laboratory where some of the flow data was collected. We also acknowledge the Center for Autoimmune Disease Research at the University of Minnesota , United States ( UMF0020624 to J.A.S.), and a bridge funding award from the University of Wisconsin Department of Biochemistry , United States, to support the mouse colony. We are especially grateful to Thomas Wolfe and Patricia Powers for establishing the “Multiple Sclerosis Research Fund in Biochemistry” at the University of Wisconsin Foundation. Without their generosity, this research could not have been performed. Appendix A Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",

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N1 - Funding Information: We extend our gratitude to Dr. René St-Arnaud (Research Center, Shriners Hospital for Children, Canada, Montréal H4A A09) for the generous gift of C57BL/6 mice with loxP sites flanking exon 8 of the Cyp27b1 gene, to Dr. Shane Hubler for his guidance on statistical analyses, and to Dr. Brigitte Huber for her thoughtful review of the manuscript prior to submission. We also thank Ms. Dagna Sheerar for her valuable assistance with the flow cytometery experiments and Ms. Heather Suchomel for her conscientious animal care services. We acknowledge the University of Wisconsin Carbone Cancer Center Support Grant P30 CA014520 , United States, for supporting the Flow Cytometry Laboratory where some of the flow data was collected. We also acknowledge the Center for Autoimmune Disease Research at the University of Minnesota , United States ( UMF0020624 to J.A.S.), and a bridge funding award from the University of Wisconsin Department of Biochemistry , United States, to support the mouse colony. We are especially grateful to Thomas Wolfe and Patricia Powers for establishing the “Multiple Sclerosis Research Fund in Biochemistry” at the University of Wisconsin Foundation. Without their generosity, this research could not have been performed. Appendix A Publisher Copyright: © 2019 Elsevier B.V.

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