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

Shelley Gorman; Sian Geldenhuys; Clare E Weeden; Michele A Grimbaldeston; Prue H Hart

doi:10.1007/s00403-018-1814-z

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

Arch Dermatol Res. 2018 Apr;310(3):221-230. doi: 10.1007/s00403-018-1814-z. Epub 2018 Feb 1.

Authors

Shelley Gorman¹, Sian Geldenhuys², Clare E Weeden², Michele A Grimbaldeston^{3

4}, Prue H Hart²

Affiliations

¹ Telethon Kids Institute, University of Western Australia, 100 Roberts Rd, Subiaco, Perth, WA, 6008, Australia. shelley.gorman@telethonkids.org.au.
² Telethon Kids Institute, University of Western Australia, 100 Roberts Rd, Subiaco, Perth, WA, 6008, Australia.
³ OMNI-Biomarker Development, Genentech Inc, South San Francisco, CA, USA.
⁴ Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.

PMID: 29392411
DOI: 10.1007/s00403-018-1814-z

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 (T_Reg) 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 T_Reg (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 + T_Reg cells and the capacity of T_Reg cells to secrete IL-9 ex vivo. However, the proportion of the IL-9 + cells of the total T_Reg cell population was small (< 1%), and the amount of IL-9 secreted by T_Reg 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 T_Reg 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.

Keywords: Contact dermatitis; Interleukin-9; Mast cells; Regulatory T cells; Vitamin D.

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology*
Dendritic Cells / immunology
Dermatitis, Contact / drug therapy*
Dermatitis, Contact / immunology
Dermatitis, Contact / pathology
Dinitrofluorobenzene / toxicity
Female
Inflammation / immunology
Inflammation / pathology
Interleukin-9 / immunology*
Mast Cells / immunology*
Mice
Mice, Inbred BALB C
Skin / immunology
Skin / pathology
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Regulatory / immunology*
Vitamin D / analogs & derivatives*
Vitamin D / pharmacology

Substances

Anti-Inflammatory Agents
Interleukin-9
Vitamin D
1,25-dihydroxyvitamin D
Dinitrofluorobenzene