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Investigating the roles of regulatory T cells, mast cells and interleukin-9 in the control of skin inflammation by vitamin D

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Abstract

Topical application of biologically active vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D)], or low-calcemic analogues, curb skin inflammation through mechanisms that involve migratory dendritic cells (DCs) and regulatory T (TReg) cells. 1,25(OH)2D also promotes immunoregulation by mast cells, and inhibits the development of T helper type-9 (Th9) cells that secrete interleukin-9 (IL-9). Here, we investigated the ability of topical 1,25(OH)2D to suppress contact dermatitis through an IL-9-dependent process, examining mast cells and IL-9-secreting T cells. Contact dermatitis was modelled in adult BALB/c female mice by initiating a “biphasic ear swelling response” following a single application of 2,4-dinitrofluorobenzene (DNFB). Topical 1,25(OH)2D (125 ng) applied to ear pinnae prior to (but not after) DNFB sensitisation suppressed the efferent phase of the ear swelling response. This dose of 1,25(OH)2D did not cause hypercalcemia. At the peak of the efferent ear swelling response, proportions of TReg (CD3 + Foxp3+) cells and numbers of mast cells were increased in ear skin of 1,25(OH)2D-treated mice. Topical 1,25(OH)2D increased the proportion of Foxp3 + IL-9 + TReg cells and the capacity of TReg cells to secrete IL-9 ex vivo. However, the proportion of the IL-9 + cells of the total TReg cell population was small (< 1%), and the amount of IL-9 secreted by TReg cells from mice treated with IL-9 was low (< 50 pg/ml). Furthermore, injection of anti-IL-9 neutralising antibody (100 µg, intraperitoneally) prior to sensitisation did not significantly reverse the suppressive effects of 1,25(OH)2D. In conclusion, topically applied 1,25(OH)2D suppressed the efferent phase of a biphasic cutaneous ear swelling response through mechanism(s) that may be dependent on mast cells and TReg cells; however, the role of IL-9 in mediating these responses is uncertain. More studies are needed to further characterise the mechanisms by which topical 1,25(OH)2D modulates cell-mediated immune responses central to its suppressive effects upon contact dermatitis.

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Abbreviations

1,25(OH)2D:

1,25-dihydroxyvitamin D

DNFB:

2,4-dinitrofluorobenzene

DCs:

Dendritic cells

EDLN or SDLN:

(Ear) or (skin)-draining lymph nodes

IL-9, IL-10:

Interleukin-9 or -10

Th9 cells:

T helper type-9 cells

TReg cells:

Regulatory T cells

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Acknowledgements

We thank Ms Maxine Crook (Princess Margaret Hospital Pathology; Subiaco, Western Australia) for the preparation and staining of tissue sections for histopathology assessment. This research was supported by: the BrightSpark Foundation; Telethon Kids Institute; University of Western Australia; the Health Department of Western Australia (to SG); and, an Australian National Health and Medical Research Council (NHMRC) Career Development Fellowship (to MAG, GNT626907). SG is currently funded by an Al & Val Rosenstrauss Fellowship from the Rebecca L Cooper Foundation.

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Authors and Affiliations

  1. Telethon Kids Institute, University of Western Australia, 100 Roberts Rd, Subiaco, Perth, WA, 6008, Australia

    Shelley Gorman, Sian Geldenhuys, Clare E. Weeden & Prue H. Hart

  2. OMNI-Biomarker Development, Genentech Inc, South San Francisco, CA, USA

    Michele A. Grimbaldeston

  3. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia

    Michele A. Grimbaldeston

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  1. Shelley Gorman
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Correspondence to Shelley Gorman.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Telethon Kids Institute at which the studies were conducted. All experiments were performed according to the ethical guidelines of the National Health and Medical Research Council of Australia and with approval from the Telethon Kids Institute Animal Ethics Committee (AEC#229).

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Gorman, S., Geldenhuys, S., Weeden, C.E. et al. Investigating the roles of regulatory T cells, mast cells and interleukin-9 in the control of skin inflammation by vitamin D. Arch Dermatol Res 310, 221–230 (2018). https://doi.org/10.1007/s00403-018-1814-z

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