Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells

Kónya, Viktória; Czarnewski, Paulo; Forkel, Marianne; Rao, Anna; Kokkinou, Efthymia; Villablanca, Eduardo J.; Almér, Sven; Lindforss, Ulrik; Friberg, Danielle; Höög, Charlotte; Bergman, Peter; Mjösberg, Jenny

doi:10.1016/j.jaci.2017.01.045

Cited by 80 publications

(57 citation statements)

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“…Biopsy retrieval and cell isolation was performed as previously described . Briefly, biopsies were collected from inflamed and/or non‐inflamed areas of the intestine during colonoscopy of IBD patients.…”

Section: Methodsmentioning

confidence: 99%

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

et al. 2019

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The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1β plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1β and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.Keywords: Aiolos r Ikaros r ILC r lenalidomide r NK cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Section: Methodsmentioning

confidence: 99%

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

et al. 2019

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“…ILC3 are typically activated by IL-1β and IL-23 to produce the effector cytokines IL-22, and to a lesser extent, IL-17A and IL-17F. In the human, these cytokines are produced by distinct subpopulations of ILC3, with IL-22 being produced by ILC3 expressing NKp44 [23, 46, 47], and IL-17A/F by NKp44 − ILC3 [23, 47]. Of note, human tonsil ILC3 produce IL-17F with little or no IL-17A, whereas human fetal ILC3 produce substantial amounts of IL-17A [48].…”

Section: Ilc3mentioning

confidence: 99%

“…Of note, human tonsil ILC3 produce IL-17F with little or no IL-17A, whereas human fetal ILC3 produce substantial amounts of IL-17A [48]. Additionally, human ILC3 produce high levels of TNF, GM-CSF [23, 47]. …”

Section: Ilc3mentioning

confidence: 99%

“…In humans, the dominating ILC3 population in the gut is IL-22-producing NKp44 + ILC3 [47], which likely, as judged from mouse studies, plays a role in intestinal homeostasis. Supporting this, appearance of IL-22-producing, gut-homing NKp44 + ILC3 in the blood of acute myeloid leukemia (AML) patients following conditioning treatment and hematopoetic stem cell transplantation (HSCT) is associated with protection against development of graft-versus-host disease (GVHD) [68].…”

Section: Ilc3mentioning

confidence: 99%

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The roles for innate lymphoid cells in the human immune system

et al. 2018

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From constituting a novel and obscure cell population, innate lymphoid cells (ILCs) are now accepted as a self-evident part of the immune system, contributing with unique and complementary functions to immunity by production of effector cytokines and interaction with other cell types. In this review, we discuss the redundant and complementary roles of the highly plastic human ILCs and their interaction with other immune cells with the ultimate aim of placing ILCs in a wider context within the human immune system.

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“…Research reveals a connection between the polymorphisms of the genes for Th17 cell-surface receptors, IL-23R, and CCR6 and susceptibility to IBD, multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis [6]. Recent work has that Vitamin D down regulates the IL-23 receptor pathway [7].…”

Section: Introductionmentioning

confidence: 99%

Metadichol, A Novel ROR Gamma Inverse Agonist and Its Applications in Psoriasis

PR¹

2017

J Clin Exp Dermatol Res

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Psoriasis affects 3% of the population worldwide, and there is no known cure. Psoriasis is associated with an increased risk of psoriatic arthritis, lymphomas, cardiovascular disease, and Crohn's disease. Psoriasis treatments today include steroid and vitamin D3 cream, ultraviolet light, and immune systemsuppressing medications such as methotrexate.The T cells responsible for psoriasis are Th1 and Th l7 cells. IL-22, produced by Th17 cells, is crucial for the proliferation of keratinocytes. IL-22 with the help of IL-17 can induce the critical events of psoriasis. To maintain Th17 cells, IL-23 is required, and it is released from tumor necrosis factor-alpha (TNF-alpha) induced pathways. The pathophysiology of psoriasis involves RORC (retinoic acid receptor-related orphan nuclear receptor gamma) as a critical transcription factor for the development of Th17 cells. FDA has approved an antibody Secukinumab ® targeting TNF-α for the treatment of psoriasis. Other FDA approved drugs are Tremfya ® targeting IL23 for treatment of moderate to severe plaque psoriasis and Taltz ® that blocks IL17 for treatment of plaque psoriasis.Metadichol ® a nanoformulation of long-chain lipid alcohols derived from food is a TNF-alpha inhibitor and also binds to Vitamin D receptor (VDR) that could have beneficial effects on Psoriasis. VDR modulates Th1-mediated inflammatory disease like psoriasis. We now present evidence that Metadichol is an inverse agonist of RORγt and AHR (Aryl Hydrocarbon Receptor) thus controlling Th17, IL17 and IL22. Being a TNF-alpha inhibitor, it can control IL23 thus blocking the significant pathways that exacerbate psoriasis. We present case studies of 7 patients afflicted with psoriasis and skin related conditions and how treatment with Metadichol resolved the underlying disease. Metadichol ® has properties that allow its use as a safe nontoxic, toxic solution to combating the growing number of psoriasis cases. TNF-a is implicated in the pathogenesis of multiple inflammatory and autoimmune conditions such as like Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. The development of TNF-α inhibitors has improved therapeutic options for patients with these conditions. However, TNF-α inhibitors are paradoxically inducing the new onset of psoriasis or worsening preexisting quiescent psoriatic diseases [13].Genomic effects of 1, 25(OH)2D3 are controlled via binding to a nuclear receptor protein, VDR (vitamin D receptor). VDR is expressed in keratinocytes, fibroblasts, Langerhans cells, sebaceous gland cells, endothelial cells and almost the entire cell types related to the skin immune system [14]. Vitamin D and analogs display in the skin effects on cellular differentiation, proliferation, regulate psoriasis and represent a standard therapy. However, there is a need for highly antiproliferative or anti-inflammatory acting vitamin D analogs that exhibit only minor calcemic activity. Selective vitamin D signaling pathways that exert little calcemic activity would...

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Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells

Abstract: 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.

Cited by 80 publications

References 71 publications

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

The roles for innate lymphoid cells in the human immune system

Metadichol, A Novel ROR Gamma Inverse Agonist and Its Applications in Psoriasis

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