Format

Send to

Choose Destination
JCI Insight. 2019 Jan 24;4(2). pii: 123390. doi: 10.1172/jci.insight.123390. [Epub ahead of print]

Disrupting the IL-36 and IL-23/IL-17 loop underlies the efficacy of calcipotriol and corticosteroid therapy for psoriasis.

Germán B1,2,3,4, Wei R1,2,3,4, Hener P1,2,3,4, Martins C5, Ye T1,2,3,4, Gottwick C6, Yang J6, Seneschal J5, Boniface K5, Li M1,2,3,4.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
2
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
3
Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France.
4
Université de Strasbourg, Illkirch, France.
5
INSERM U1035, BMGIC, Equipe Immunodermatologie ATIP-AVENIR, Hôpital Saint-André Service de Dermatologie, Université de Bordeaux, France.
6
BIOSS Centre for Biological Signalling Studies, Department of Molecular Immunology, Institute of Biology III, Faculty of Biology, University of Freiburg, Freiburg, Germany.

Abstract

Psoriasis is one of the most common skin inflammatory diseases worldwide. The vitamin D3 analog calcipotriol has been used alone or in combination with corticosteroids in treating plaque psoriasis, but how it suppresses psoriatic inflammation has not been fully understood. Using an experimental mouse psoriasis model, we show that topical calcipotriol inhibited the pivotal IL-23/IL-17 axis and neutrophil infiltration in psoriatic skin, and interestingly, such effects were mediated through the vitamin D receptor (VDR) in keratinocytes (KCs). We further reveal that IL-36α and IL-36γ, which have recently emerged as key players in psoriasis pathogenesis, were effectively repressed by calcipotriol via direct VDR signaling in mouse KCs. Accordingly, calcipotriol treatment suppressed IL-36α/γ expression in lesional skin from patients with plaque psoriasis, which was accompanied by a reduced IL-23/IL-17 expression. In contrast, dexamethasone indirectly reduced IL-36α/γ expression in mouse psoriatic skin through immune cells. Furthermore, we demonstrate that calcipotriol and dexamethasone, in combination, synergistically suppressed the expression of IL-36α/γ, IL-23, and IL-17 in the established mouse psoriasis. Our findings indicate that the combination of calcipotriol and corticosteroid efficiently disrupts the IL-36 and IL-23/IL-17 positive feedback loop, thus revealing a mechanism underlying the superior efficacy of calcipotriol and corticosteroid combination therapy for psoriasis.

KEYWORDS:

Cytokines; Dermatology; Inflammation; Skin

PMID:
30674716
DOI:
10.1172/jci.insight.123390
Free full text

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation
Loading ...
Support Center