Transcriptomics identifies blunted immunomodulatory effects of ...
Yeh, W. Z. et al. Immunoregulatory effects and therapeutic potential of vitamin D in multiple sclerosis. Br. J. Pharmacol. 177, 4113–4133 (2020).
Article CAS PubMed PubMed Central Google Scholar
Veldman, C. M., Cantorna, M. T. & DeLuca, H. F. Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system. Arch. Biochem. Biophys. 374, 334–338 (2000).
Article CAS PubMed Google Scholar
Booth, D. R. et al. Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases. Genes Immun. 17, 213–219 (2016).
Article CAS PubMed PubMed Central Google Scholar
Baeke, F. et al. Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system. J. Steroid Biochem. Mol. Biol. 121, 221–227 (2010).
Article CAS PubMed Google Scholar
Liu, P. T., Stenger, S., Tang, D. H. & Modlin, R. L. Cutting edge: Vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J. Immunol. 179, 2060–2063 (2007).
Article CAS PubMed Google Scholar
Penna, G. & Adorini, L. 1α,25-Dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).
Article CAS PubMed Google Scholar
Jeffery, L. E. et al. 1,25-dihydroxyvitamin D3 and interleukin-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 183, 5458–5467 (2009).
Article CAS PubMed Google Scholar
Prietl, B. et al. High-dose cholecalciferol supplementation significantly increases peripheral CD4+ Tregs in healthy adults without negatively affecting the frequency of other immune cells. Eur. J. Nutr. 53, 751–759 (2014).
Article CAS PubMed Google Scholar
Allen, A. C. et al. A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers. Mult. Scler. 18, 1797–1800 (2012).
Article PubMed Google Scholar
Munger, K. L., Levin, L. I., Hollis, B. W., Howard, N. S. & Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296, 2832–2838 (2006).
Article CAS PubMed Google Scholar
da Costa, D. S. M. M. et al. Vitamin D modulates different IL-17-secreting T cell subsets in multiple sclerosis patients. J. Neuroimmunol. 299, 8–18 (2016).
Article PubMed Google Scholar
Kickler, K., Ni Choileain, S., Williams, A., Richards, A. & Astier, A. L. Calcitriol modulates the CD46 pathway in T cells. PLoS One 7, e48486 (2012).
Article CAS PubMed PubMed Central Google Scholar
Jagannath, V. A. et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD008422.pub3 (2018).
Article PubMed PubMed Central Google Scholar
Hupperts, R. et al. Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a. Neurology https://doi.org/10.1212/WNL.0000000000008445 (2019).
Article PubMed PubMed Central Google Scholar
Subramanian, A. et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. 102, 15545–15550 (2005).
Article CAS PubMed PubMed Central Google Scholar
International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 365, eaav7188 (2019).
Article PubMed Central Google Scholar
Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, 17 (2005).
Article MathSciNet Google Scholar
Langfelder, P. & Horvath, S. Eigengene networks for studying the relationships between co-expression modules. BMC Syst. Biol. 1, 54 (2007).
Article PubMed PubMed Central Google Scholar
Kriegler, M., Perez, C., DeFay, K., Albert, I. & Lu, S. D. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: Ramifications for the complex physiology of TNF. Cell 53, 45–53 (1988).
Article CAS PubMed Google Scholar
Calzascia, T. et al. TNF-α is critical for antitumor but not antiviral T cell immunity in mice. J. Clin. Investig. 117, 3833–3845 (2007).
CAS PubMed PubMed Central Google Scholar
Park, K. M. & Bowers, W. J. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal. 22, 977–983 (2010).
Article CAS PubMed PubMed Central Google Scholar
Schioppa, T. et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc. Natl. Acad. Sci. 108, 10662–10667 (2011).
Article CAS PubMed PubMed Central Google Scholar
Sharief, M. K. & Hentges, R. Association between tumor necrosis factor-α and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325, 467–472 (1991).
Article CAS PubMed Google Scholar
Rieckmann, P. et al. Tumor necrosis factor-α messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Ann. Neurol. 37, 82–88 (1995).
Article CAS PubMed Google Scholar
Huang, W.-X., Huang, P., Link, H. & Hillert, J. Cytokine analysis in multiple sclerosis by competitive RT-PCR: A decreased expression of IL-10 and an increased expression of TNF-α in chronic progression. Mult. Scler. 5, 342–348 (1999).
CAS PubMed Google Scholar
van Oosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996).
Article PubMed Google Scholar
Arnett, H. A. et al. TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci. 4, 1116–1122 (2001).
Article CAS PubMed Google Scholar
Müller, K. et al. 1,25-dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level. Cytokine 4, 506–512 (1992).
Article PubMed Google Scholar
Lysandropoulos, A. P. et al. Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects. J. Neuroimmunol. 233, 240–244 (2011).
Article CAS PubMed Google Scholar
Peterson, C. A. & Heffernan, M. E. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J. Inflamm. 5, 10 (2008).
Article Google Scholar
Yang, W. S. et al. 1,25-Dihydroxyvitamin D3 causes ADAM10-dependent ectodomain shedding of tumor necrosis factor receptor 1 in vascular smooth muscle cells. Mol. Pharmacol. 87, 533–542 (2015).
Article PubMed Google Scholar
Song, G. G., Bae, S.-C. & Lee, Y. H. Association between vitamin D intake and the risk of rheumatoid arthritis: A meta-analysis. Clin. Rheumatol. 31, 1733–1739 (2012).
Article PubMed Google Scholar
Ananthakrishnan, A. N. et al. Higher predicted vitamin d status is associated with reduced risk of Crohn’s disease. Gastroenterology 142, 482–489 (2012).
Article CAS PubMed Google Scholar
Kamen, D. L. et al. Vitamin D deficiency in systemic lupus erythematosus. Autoimmun. Rev. 5, 114–117 (2006).
Article CAS PubMed Google Scholar
Umar, M. et al. Vitamin D and the pathophysiology of inflammatory skin diseases. SPP 31, 74–86 (2018).
CAS Google Scholar
Hahn, J. et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 376, e066452 (2022).
Article PubMed PubMed Central Google Scholar
Dimitrov, V. et al. Vitamin D-regulated gene expression profiles: Species-specificity and cell-specific effects on metabolism and immunity. Endocrinology 162, bqaa218 (2021).
Article PubMed Google Scholar
von Essen, M. R. et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat. Immunol. 11, 344–349 (2010).
Article Google Scholar
Richards, J. B. et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am. J. Clin. Nutr. 86, 1420–1425 (2007).
Article CAS PubMed Google Scholar
Jirmanova, L., Giardino Torchia, M. L., Sarma, N. D., Mittelstadt, P. R. & Ashwell, J. D. Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation. Blood 118, 3280–3289 (2011).
Article CAS PubMed PubMed Central Google Scholar
Zhang, Y. et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J. Immunol. 188, 2127–2135 (2012).
Article CAS PubMed Google Scholar
Ding, C., Wilding, J. P. H. & Bing, C. 1,25-Dihydroxyvitamin D3 protects against macrophage-induced activation of NFκB and MAPK signalling and chemokine release in human adipocytes. PLoS One 8, e61707 (2013).
Article CAS PubMed PubMed Central Google Scholar
Xin, L. et al. 1,25-Dihydroxy vitamin D3 attenuates the oxidative stress-mediated inflammation induced by PM2.5 via the p38/NF-κB/NLRP3 pathway. Inflammation 42, 702–713 (2019).
Article CAS PubMed Google Scholar
Joshi, S. et al. 1,25-Dihydroxyvitamin D3 ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol. Cell. Biol. 31, 3653–3669 (2011).
Article CAS PubMed PubMed Central Google Scholar
Takeuchi, A. et al. Nuclear factor of activated T cells (NFAT) as a molecular target for 1α,25-dihydroxyvitamin D3-mediated effects. J. Immunol. 160, 209–218 (1998).
Article CAS PubMed Google Scholar
Matilainen, J. M., Räsänen, A., Gynther, P. & Väisänen, S. The genes encoding cytokines IL-2, IL-10 and IL-12B are primary 1α,25(OH)2D3 target genes. J. Steroid Biochem. Mol. Biol. 121, 142–145 (2010).
Article CAS PubMed Google Scholar
Alroy, I., Towers, T. L. & Freedman, L. P. Transcriptional repression of the interleukin-2 gene by vitamin D3: Direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol. Cell. Biol. 15, 5789–5799 (1995).
Article CAS PubMed PubMed Central Google Scholar
Ikeda, U. et al. 1α,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells. Immunol. Lett. 134, 7–16 (2010).
Article CAS PubMed Google Scholar
Palmer, M. T. et al. Lineage-specific effects of 1,25-dihydroxyvitamin d3 on the development of effector CD4 T cells. J. Biol. Chem. 286, 997–1004 (2011).
Article CAS PubMed Google Scholar
Müller, K., Ødum, N. & Bendtzen, K. 1,25-Dihydroxyvitamin D3 selectively reduces interleukin-2 levels and proliferation of human T cell lines in vitro. Immunol. Lett. 35, 177–182 (1993).
Article PubMed Google Scholar
Urry, Z. et al. The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur. J. Immunol. 42, 2697–2708 (2012).
Article CAS PubMed PubMed Central Google Scholar
Chauss, D. et al. Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells. Nat. Immunol. 23, 62–74 (2022).
Article CAS PubMed Google Scholar
Bhargava, P. et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. Mult. Scler. 22, 753–760 (2016).
Article CAS PubMed Google Scholar
Bhargava, P., Fitzgerald, K. C., Calabresi, P. A. & Mowry, E. M. Metabolic alterations in multiple sclerosis and the impact of vitamin D supplementation. JCI Insight 2, e95302 (2017).
Article PubMed PubMed Central Google Scholar
Lu, M., Shi, H., Taylor, B. V. & Körner, H. Alterations of subset and cytokine profile of peripheral T helper cells in PBMCs from Multiple Sclerosis patients or from individuals with MS risk SNPs near genes CYP27B1 and CYP24A1. Cytokine 153, 155866 (2022).
Article CAS PubMed Google Scholar
Mu, Z. et al. The impact of cell type and context-dependent regulatory variants on human immune traits. Genome Biol. 22, 122 (2021).
Article CAS PubMed PubMed Central Google Scholar
Ewing, E. et al. Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. EBioMedicine 43, 411–423 (2019).
Article PubMed PubMed Central Google Scholar
Kim, D. et al. Peripheral T-cells, B-cells, and monocytes from multiple sclerosis patients supplemented with high-dose vitamin d show distinct changes in gene expression profiles. Nutrients 14, 4737 (2022).
Article MathSciNet CAS PubMed PubMed Central Google Scholar
Polman, C. H. et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann. Neurol. 69, 292–302 (2011).
Article PubMed PubMed Central Google Scholar
Andrews, S. FastQC: A Quality Control Tool for High Throughput Sequence Data (2010).
Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525–527 (2016).
Article CAS PubMed Google Scholar
R Core Team. R: A Language and Environment for Statistical Computing (2019).
Soneson, C., Love, M. I. & Robinson, M. D. Differential analyses for RNA-seq: Transcript-level estimates improve gene-level inferences. F1000Res 4, 1521 (2016).
Article PubMed Central Google Scholar
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
Article CAS PubMed Google Scholar
Risso, D., Ngai, J., Speed, T. P. & Dudoit, S. Normalization of RNA-seq data using factor analysis of control genes or samples. Nat. Biotechnol. 32, 896–902 (2014).
Article CAS PubMed PubMed Central Google Scholar
Eisenberg, E. & Levanon, E. Y. Human housekeeping genes, revisited. Trends Genet. 29, 569–574 (2013).
Article CAS PubMed Google Scholar
Ramagopalan, S. V. et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res. 20, 1352–1360 (2010).
Article CAS PubMed PubMed Central Google Scholar
Neme, A., Seuter, S. & Carlberg, C. Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor. Biochim. Biophys. Acta (BBA) Gene Regul. Mech. 1860, 952–961 (2017).
Article CAS Google Scholar
Shirvani, A., Kalajian, T. A., Song, A. & Holick, M. F. Disassociation of vitamin D’s calcemic activity and non-calcemic genomic activity and individual responsiveness: A randomized controlled double-blind clinical trial. Sci. Rep. 9, 17685 (2019).
Article PubMed PubMed Central Google Scholar
Gandolfo, L. C. & Speed, T. P. RLE plots: Visualizing unwanted variation in high dimensional data. PLoS One 13, e0191629 (2018).
Article PubMed PubMed Central Google Scholar
Cunningham, F. et al. Ensembl 2022. Nucleic Acids Res. 50, D988–D995 (2022).
Article CAS PubMed Google Scholar
Durinck, S., Spellman, P. T., Birney, E. & Huber, W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat. Protoc. 4, 1184–1191 (2009).
Article CAS PubMed PubMed Central Google Scholar
Lun, A. T. L., Chen, Y. & Smyth, G. K. It’s DE-licious: A recipe for differential expression analyses of RNA-seq experiments using quasi-likelihood methods in edgeR. In Statistical Genomics: Methods and Protocols (eds Mathé, E. & Davis, S.) 391–416 (Springer, 2016). https://doi.org/10.1007/978-1-4939-3578-9_19.
Chapter Google Scholar
Evelo, C. et al. Vitamin D metabolism (Homo sapiens)—WikiPathways. https://www.wikipathways.org/index.php/Pathway:WP1531
Langfelder, P. & Horvath, S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinform. 9, 559 (2008).
Article Google Scholar
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B (Methodology) 57, 289–300 (1995).
MathSciNet Google Scholar
Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).
Article CAS PubMed PubMed Central Google Scholar
Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).
Article CAS PubMed PubMed Central Google Scholar
Wu, T. et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).
CAS PubMed PubMed Central Google Scholar
Wickham, H. ggplot2 (Springer International Publishing, 2016). https://doi.org/10.1007/978-3-319-24277-4.
Book Google Scholar
Chen, J., Bardes, E. E., Aronow, B. J. & Jegga, A. G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 37, W305–W311 (2009).
Article CAS PubMed PubMed Central Google Scholar
Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016).
Article CAS PubMed Google Scholar