Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1

Kılıc, A.; Halu, A.; De Marzio, M.; Maiorino, E.; Duvall, M. G.; Brüggemann, T. R.; Rojas Quintero, J. J.; Chase, R.; Mirzakhani, H.; Özge Sungur, A.; Koepke, J.; Nakano, T.; Peh, H. Y.; Krishnamoorthy, N.; Abdulnour, R.-E.; Georgopoulos, K.; Litonjua, A. A.; Demay, M. B.; Renz, H.; Levy, B. D.; Weiss, S. T.

doi:10.1101/2022.05.22.491886

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bioRxiv · 10.1101/2022.05.22.491886

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1

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Abstract

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (1). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D mediated immunoregulation. Here we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases (2-4). We demonstrate increased vitamin D receptor (VDR) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3 encoded protein Aiolos to suppress IL-2-signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders. One Sentence SummaryVitamin D regulates two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, that are associated with autoimmune and chronic inflammatory diseases.

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Kılıc, A., Halu, A., De Marzio, M., Maiorino, E., Duvall, M. G., Brüggemann, T. R., Rojas Quintero, J. J., Chase, R., Mirzakhani, H., Özge Sungur, A., Koepke, J., Nakano, T., Peh, H. Y., Krishnamoorthy, N., Abdulnour, R.-E., Georgopoulos, K., Litonjua, A. A., Demay, M. B., Renz, H., Levy, B. D., Weiss, S. T.. 2022-05-24. Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1. https://doi.org/10.1101/2022.05.22.491886

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