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Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells
Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
Sci Life Lab, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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2018 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 141, no 1, p. 279-292Article in journal (Refereed) Published
Abstract [en]

Background: Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. Objective: We set out to define the role of 1 alpha,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus Il-1 beta stimulation. Methods: Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. Results: ILC3s stimulated with IL-23 plus IL-1 beta upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1 beta signaling pathway, as well as the IL-1 beta-inducible cytokines IL-6, IL-8, and macrophage inflammatory protein IL/1 beta. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. Conclusion: In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.

Place, publisher, year, edition, pages
MOSBY-ELSEVIER , 2018. Vol. 141, no 1, p. 279-292
Keywords [en]
Innate lymphoid cells; inflammatory bowel diseases; vitamin D receptor; IL-22
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-144896DOI: 10.1016/j.jaci.2017.01.045ISI: 000419312200033PubMedID: 28433688OAI: oai:DiVA.org:liu-144896DiVA, id: diva2:1181661
Note

Funding Agencies|European Unions Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [655677]; Austrian Science Fund FWF [P25531-B23]; Swedish Research Council; Swedish Cancer Foundation; Swedish Foundation for Strategic Research; Knut and Alice Wallenberg Foundation; Swedish Society for Medical Research

Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-02-09

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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health Sciences
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