Vitamin D downregulates the IL-23 receptor pathway in human mucosal ILC3

Publication date: Available online 20 April 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Viktoria Konya, Paulo Czarnewski, Marianne Forkel, Anna Rao, Efthymia Kokkinou, Eduardo J. Villablanca, Sven Almer, Ulrik Lindforss, Danielle Friberg, Charlotte Höög, Peter Bergman, Jenny Mjösberg
BackgroundVitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident ILC3 play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy.ObjectiveWe set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3 to IL-23 plus IL-1β stimulation.MethodsTranscriptomes of sorted tonsil ILC3 were assessed by microarray analysis. ILC3 cytokine production, proliferation and differentiation were determined by flow cytometry, ELISA and multiplex immunoassay. Intestinal cell suspensions and ILC3 sorted from gut biopsies of IBD patients were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection.ResultsILC3 stimulated with IL-23 plus IL-1β upregulated the vitamin D receptor (VDR) and responded to 1,25D with downregulation of the IL-23 receptor (IL-23R) pathway. Consequently, 1,25D suppressed the IL-22, IL-17F and GM-CSF production from tonsil and gut ILC3. In parallel, 1,25D upregulated genes linked to the IL-1β signaling pathway as well as the IL-1β-inducible cytokines IL-6, IL-8 and MIP-1α/β. 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 IBD patients with active inflammation.ConclusionIn the light of the beneficial targeting of IL-23/12 in IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23R pathway, providing a novel mechanism for how ILC3 could be manipulated to regulate intestinal inflammation.

Teaser

We have unraveled the detailed mechanisms behind how vitamin D efficiently suppresses IL-23 receptor signaling in gut innate lymphoid cells, providing incitement for vitamin D supplementation as a therapeutic approach in IBD.


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