Effective narrow-band UVB radiation therapy suppresses the IL-23/IL-17 axis in normalized psoriasis plaques

Abstract

Narrow-band UVB radiation (NB-UVB) therapy offers a well-established treatment modality for psoriasis. However, despite the common use of this form of treatment, the mechanism of action of NB-UVB is not well understood. We studied a group of 14 patients with moderate-to-severe psoriasis treated with carefully titrated and monitored NB-UVB for 6 weeks. Lesional plaques were classified as normalized (n=8) or nonresponsive (n=6) based on their histological improvement and normalization. We characterized lesional myeloid dendritic cells (DCs) and T cells and their inflammatory mediators using immunohistochemistry and real-time PCR. NB-UVB suppressed multiple parameters of the IL-23/IL-17 pathway in normalized plaques, but not in nonresponsive plaques. NB-UVB decreased the numbers of CD11c(+) DCs, specifically CD1c(-)CD11c(+) "inflammatory" DCs, and their products, IL-20, inducible nitric oxide synthase, IL-12/23p40, and IL-23p19. Furthermore, effective NB-UVB suppressed IL-17 and IL-22 mRNAs, which strongly correlated with lesion resolution. Therefore, in addition to its known role in suppressing IFN-γ production, NB-UVB radiation therapy can also target the IL-17 pathway to resolve psoriatic inflammation.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub.

Trial registration: ClinicalTrials.gov NCT00220025.

Conflict of interest statement

Conflict of interest

The authors do not have any conflict of interest.

Figures

Figure 1. Classification of normalized and non-responsive plaques

(a–b) Histological response was measured at baseline in non-lesional (NL) and lesional (LS) skin and skin 6 weeks post-treatment (week 6). Representative histology and immunohistochemistry showing hematoxylin and eosin (H&E) and K16 expression in (a) normalized plaques and (b) non-responsive plaques. Scale bar = 100μm. (c) Epidermal thickness of normalized (norm, black bars, n=7) and non-responsive plaques (non-resp, white bars, n=6) before and after NB-UVB therapy. Error bars represent the mean ± SEM. NL and wk6 values are compared to LS. (*) P<0.05, (***) P<0.001. (d) K16 mRNA expression normalized to hARP in both normalized (black bars) and non-responsive plaques (white bars). Error bars represent the mean ± SEM.

Figure 2. Inflammatory myeloid DCs are reduced in normalized plaques

(a, b) Representative immunohistochemistry of CD1c+ and CD11c+ cells. Bar, 100μm (c,d) Quantification of dermal CD1c+ or CD11c+ cells in normalized (black) and non-responsive plaques (white). Each circle represents a plaque. NL and wk6 are compared to LS. (**) P<0.01, (***) P<0.001. (e) CD11c+CD1c− cell numbers were calculated by subtracting CD1c+ counts from CD11c+ counts. (*) P<0.05. (f) Two-color immunofluorescence of CD11c (green) and CD1c (red) of normalized plaque. Cells co-expressing both markers appear yellow due to the superimposition of both green and red signals. Inset, high power magnification of double positive cells. The white line delineates the dermo-epidermal junction. Scale bar = 100μm.

Figure 3. Decreased DC products in normalized plaques

(a) mRNA expression levels normalized to hARP for the inflammatory DC products, iNOS, IL-20, IL-12/23p40, and IL-23p19 in both normalized (black bars, n=8) and non-responsive plaques (white bars, n=6). Error bars represent the mean ± SEM. NL and wk6 levels are compared to LS. (*) P<0.05, (**) P<0.01, (***) P<0.001. (b–c) Two-color immunofluorescence of CD11c+ myeloid DCs (red) with IL-23 subunits in a normalized plaque, (b) p40 and (c) p19 (green), demonstrating coexpression in baseline LS skin (yellow cells), which is diminished by week 6 post-therapy. Antibodies conjugated with a fluorochrome gave background epidermal fluorescence. The white line delineates the dermal epidermal junction. Inset, high power magnification of double positive cells. Scale bar = 100μm.

Figure 4. T cells are reduced in normalized plaques

(a) Representative immunohistochemistry of CD3+ cells in NL, LS, and wk6 skin of a normalized plaque. Scale bar = 100μm. (b) Quantification of CD3+ T cell counts per mm of skin in both normalized (black circles) and non-responsive plaques (white circles). NL and wk6 counts are compared to LS. (**) P<0.01, (***) P<0.001. (c) Response scores were correlated with μ-scores for CD3+ cell counts. Spearman correlation coefficients (r) and p values are shown.

Figure 5. Decreased IL-17 and IL-22 following therapy

(a) mRNA expression levels normalized to hARP for the T cell products, IL-17, IFN-γ, and IL-22 in both normalized (black bars, n=8) and non-responsive plaues (white bars, n=6) in NL, LS, and wk6 skin. Error bars represent the mean ± SEM. NL and wk6 levels are compared to LS. (**) P<0.01, (***) P<0.001. (b) Response scores were correlated with μ-scores for mRNA expression. Spearman correlation coefficients (r) and p values are shown.