PT  - JOURNAL ARTICLE
AU  - Ayşe Kılıç
AU  - Arda Halu
AU  - Margherita De Marzio
AU  - Enrico Maiorino
AU  - Melody G. Duvall
AU  - Thayse Brueggemann
AU  - Joselyn J. Rojas Quintero
AU  - Robert Chase
AU  - Hooman Mirzakhani
AU  - Ayse Özge Sungur
AU  - Janine Koepke
AU  - Taiji Nakano
AU  - Hong Yong Peh
AU  - Nandini Krishnamoorthy
AU  - Raja-Elie Abdulnour
AU  - Katia Georgopoulos
AU  - Augusto A. Litonjua
AU  - Marie B. Demay
AU  - Harald Renz
AU  - Bruce D. Levy
AU  - Scott. T Weiss
TI  - Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1
AID  - 10.1101/2022.05.22.491886
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.22.491886
4099  - http://biorxiv.org/content/early/2022/05/24/2022.05.22.491886.short
4100  - http://biorxiv.org/content/early/2022/05/24/2022.05.22.491886.full
AB  - 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.Competing Interest StatementDr. Weiss receives royalties from UpToDate and is an investor in Histolix. All other authors declare no competing interests.