Evidence for a role of autoinflammation in early-phase psoriasis

Abstract

Psoriasis is a common, inflammatory immune-mediated skin disease mainly presenting with plaques whose pathogenesis is based on the central role of the interleukin (IL)-23/IL-17 axis. However, the mechanisms acting in papular lesions of early-phase psoriasis are not fully understood. The aim of this study was to assess the involvement of autoinflammation, a state of sterile inflammation mainly driven by IL-1 over-production that has been recently hypothesized to act in the early phase of disease. Lesional skin of 10 patients with recent onset, untreated psoriasis has been investigated for expression of IL-1β, IL-17, IL-23 and other cytokines involved in the disease in comparison with normal skin of 10 healthy controls using a protein array method. Immunohistochemical phenotyping of inflammatory infiltrate and co-localization experiments with immunofluorescence confocal microscopy were conducted. IL-1β was significantly more expressed in psoriasis than in normal skin (P < 0·0001). The chemokine IL-8 was also over-expressed in psoriasis (P = 0·03) while IL-12, IL-17, IL-23, tumour necrosis factor-α and interferon-γ were only slightly more expressed in psoriasis than in normal skin, without reaching statistical significance. The inflammatory infiltrate consisted mainly of neutrophils with a relevant number of macrophages and dendritic cells and only scattered, predominantly T helper 1 lymphocytes. IL-1β co-localized mainly with CD66b, a neutrophil marker, suggesting that neutrophils were the major source of this cytokine. IL-1β over-expression in combination with low expression of cytokines that are predominant in late-phase plaque psoriasis may support the role of autoinflammation in early-phase disease, possibly paving the way to randomized trials with IL-1 antagonists.

Keywords: autoinflammatory disease; cytokines; neutrophils; skin.

Figure 1

(a,b) Interleukin (IL)‐1β and IL‐8 in homogenate samples of psoriasis lesional skin of 10 patients, showing a statistically significant higher expression than in normal skin (NS) of 10 controls. (c–f) Expression levels of IL‐12, IL‐17, tumour necrosis factor (TNF)‐α and interferon (IFN) ‐γ are higher in psoriasis than in NS, but without reaching statistical significance. Signal intensity values for each cytokine were obtained transforming fluorescent signals into numerical data by means of a data extraction software.

Figure 2

Immunohistochemical analysis of the inflammatory infiltrate and cytokine expression assessment in early‐phase psoriasis: (a) numerous macrophages expressing CD14 are evident in the superficial and papillary dermis. (b) CD11c⁺ dendritic cells are visible both in the dermis and epidermis. (c) Plasmacytoid dendritic cells, stained with anti‐CD123 monoclonal antibody, are abundantly represented in the dermis, particularly around vessels and at the top of dermal papillae. (d) Strong dermal expression of interleukin (IL)‐1β. (e) Scattered cells are positive with the anti‐IL‐17 monoclonal antibody. (f) Low dermal expression of interferon (IFN)‐γ.

Figure 3

Immunofluorescence staining (left panel) and confocal analysis (right panel) for interleukin (IL)‐1β (red) and CD66b (green) in formalin‐fixed, paraffin‐embedded tissues of psoriasis lesional skin. Nuclei were stained with Toto‐3 (blue). Representative images at small magnification showing neutrophils both in the dermis and in the epidermis (left panels). CD66b⁺ neutrophils expressing IL‐1β are uniformly distributed in the skin (yellow). (a–f). Squared areas are visible at higher magnification in confocal laser scanning micrographs (right panels).

Figure 4

Scanning micrograph of immunofluorescent staining with CD1a (green) and interleukin (IL)‐1β (red) shows a large number of double positive cells (yellow). In the right panel confocal laser analysis shows in detail some double‐labelled cells.

Figure 5

CD163/68 (green) and interleukin (IL)‐1β (red) double‐label immunofluorescence staining. Confocal analysis zoomed view in the right panel. High number of CD163‐positive cells, few of which express IL‐1β, are seen in the dermis.