Introduction

Psoriasis affects skin with various phenotypes, and is associated with significant comorbidities1. It is a common disease, affecting 2%–3% of the population worldwide, without distinction of age, sex or ethnicity. Different types of psoriasis exist including plaque psoriasis (or psoriasis vulgaris), the most prevalent and pustular psoriasis (PP), considered as more resistant and particularly difficult to treat. PP, characterized by neutrophil-rich pustules, accounts for only a small fraction of cases but can be life-threatening when extensive2. PP is strongly associated with certain predisposing genetic factors, such as loss-of-function mutations in IL36RN – the interleukin 36 receptor antagonist3, or mutations in CARD14 (caspase recruitment domain-containing protein 14), AP1S3 (adapter protein complex 1 subunit sigma 3) or SERPINA3 (serine protease inhibitor gene serpin family A member 3)4. Despite major advances in our understanding of its pathogenesis and treatment5, psoriasis remains a common chronic disease whose causes have yet to be fully elucidated.

Psoriasis is characterized by abnormal keratinocyte proliferation and immune cell recruitment in the dermis and epidermis. The pathogenesis of psoriasis is complex and involves the interaction of keratinocytes, immune cells, and other skin resident cells. The pathogenic interleukin (IL)−23/IL-17 axis has been identified as playing a key role in psoriasis. The production of TNF-α and IL-23 by dendritic cells (DC) leads to activation of T-helper type 1 (Th1) and type 17 (Th17) cells and subsequent secretion of inflammatory cytokines, including TNF-α, IL-17, and IL-22. These cytokines (especially IL-17) then activate keratinocytes, which produce antimicrobial peptides, cytokines, and chemokines, thereby contributing to the amplification of inflammation. In addition to the TNF-α/IL-23/IL-17/IL-22 pathway, IL-36 and IL36RN are currently the focus of much attention6. Beyond the loss-of-function mutations in IL36RN in PP, IL-36 is also upregulated in plaque psoriasis and the functional activation of IL-36R might contribute to the persistence and perpetuation of psoriatic inflammation together with the TNF-α/IL-23/IL-17/IL-22 axis.

Chemokines, in particular CXCL1, are believed to be secreted in response to IL-17 and recruit neutrophils to the lesional skin. Bridging important pathogenic functions of the innate and adaptive immune systems, neutrophils exhibit complicated interactions with regulatory networks that underlie psoriatic pathophysiology7. Over the last decades, it has been assumed that immune cells drive psoriasis and keratinocytes follow their cues; however, recent evidence shows that keratinocytes can play an important triggering role in such psoriasis immune inflammatory cascades8.

Remarkably, studies going back as far as fifty years have reported increased iron concentrations in psoriatic epidermis compared to controls9,10,11. Hepcidin (encoded by the hamp gene) is a key hormonal peptide, mainly produced by the liver, that maintains systemic iron homeostasis. In conditions of high iron, the production of hepatic hepcidin in the plasma blocks iron absorption from the duodenum and iron release from macrophages. Hepcidin acts on ferroportin (FPN)—the only known cellular iron exporter—to inhibit cellular iron efflux. The efflux of iron out of the cells is controlled by hepcidin binding to ferroportin through two mechanisms: degradation of ferroportin by hepcidin-induced endocytosis12 and occlusion of the open-outward conformation of ferroportin by hepcidin13. Hepatic hepcidin is also induced by select pro-inflammatory cytokines, such as IL-1β or IL-6, and is considered the mediator of anemia of inflammation14. Apart from the liver, many cells and tissues can express hepcidin locally under pathological conditions, such as infection or inflammation, where hepcidin may participate in local iron regulation. To determine the contribution of these hepcidin-producing tissues in body iron homeostasis, we previously developed a mouse model in which the hepcidin gene can be conditionally inactivated15. We recently discovered that hepcidin can be produced by keratinocytes and plays a critical role against bacterial infection by promoting keratinocyte production of CXCL1 and recruitment of neutrophils16. In psoriasis, few studies have explored plasma hepcidin levels within the context of anemia of inflammation17,18,19, but the expression and role of skin hepcidin and iron in the pathogenesis of psoriasis remain to be investigated. Using in vitro approaches, in vivo genetic mouse models, transcriptomics, as well as human 3D organotypic skin model and psoriasis skin biopsies, we found that skin hepcidin has a key role in the initiation of psoriasiform skin inflammation.

Results

Hepcidin expression is increased in the skin of psoriasis patients

Hepcidin expression in biopsies of lesioned skin from patients with psoriasis vulgaris or PP, and in skin specimens from healthy controls, for individuals in different age groups and of either sex, was immunohistochemically assessed (Fig. 1, Supplementary Table 1). Hepcidin expression was highest in keratinocytes, the main cells of the epidermis (Fig. 1a). Hepcidin was mildly expressed in the lesional skin of psoriasis vulgaris patients (Fig. 1a, left) and highly expressed in PP patients (Fig. 1a right). The overexpression in psoriasis patients was correlated with a decrease in FPN expression (Fig. 1a). Interestingly, hepcidin quantified expression was significantly positively correlated to epidermis thickness (Fig. 1b). In addition, in a large cohort of vulgaris psoriasis patients available from a public database20, we also found that hepcidin expression was also increased at the mRNA level in the lesional skin compared to normal skin (Supplementary Fig. 1a). Interestingly, hepcidin expression was the most significantly positively correlated with Il36a and Il23, among different key psoriasis cytokines tested (Supplementary Fig. 1b). We also analyzed mRNA hepcidin levels in lesional skin from PP patients whose mutational status was known for some of them (Supplementary Table 2) and compared them to normal skin. Hepcidin expression was significantly induced in the lesional vs normal skin of PP, with the highest expression in the patients with the IL36RN mutation (Fig. 1c)