## 3 Involvement of IL-1 Family Cytokines in Inflammatory Dermatoses  
### Soriasis  
Psoriasis is a chronic inflammatory multisystem disorder with an immunogenic basis and a pathogenesis characterized by unbalanced interactions between the innate and the adaptive immune systems. The clinical presentation of psoriasis is morphologically and topographically heterogeneous; the main variants are plaque psoriasis--also known as psoriasis vulgaris--and pustular psoriasis (PP). Although there is frequent clinical overlap, their clinical, genetic, and pathogenetic distinguishing features suggest that they are in fact distinct entities [36; 40; 41]. In the pathogenesis of plaque psoriasis, there is a predominant involvement of the adaptive immune system, with a critical role of the IL-17/23 axis. Th1 and Th17 lymphocytes release TNF, IL-17, and IL-22, promoting proliferation of KCs and secretion of proinflammatory chemokines that lead to a self-amplification loop [42]. In contrast, autoinflammation and innate immune system activation are the main drivers of PP, with neutrophil infiltration of the epidermis and IL-36 and IL-1 cytokines acting as key pathogenic orchestrators of the disease [43].  
The effects of several members of the IL-1 cytokine family have been studied in both animal and human models of psoriasis. Murine models have shown that IL-1\(\alpha\) is able to initiate spontaneous cutaneous inflammation with histological similarities to psoriasis lesions and to stimulate KCs to induce potent proinflammatory responses [44; 45]. IL-1\(\beta\) also stimulates epidermal KCs to secrete inflammatory chemokines and has proven to be critical in inducing Th17 and \(\gamma\)8T17 cell differentiation and effector functions [45]. Moreover, IL-1 cytokines can stimulate mast cells to produce IL-6, tumor necrosis factor (TNF), and IL-33 without degranulation [38]. Overexpression of IL-18 has been detected in both skin lesions and peripheral blood of psoriasis patients, with IL-18 serum levelsdirectly correlating with psoriasis severity [46]. In a mouse model, IL-18 also induced prominent inflammation, with increased expression of IFNy and enhancement of psoriasis-like epidermal hyperplasia [47]. IL-33 also appears to be involved in the pathogenesis of psoriasis, participating in the crosstalk between innate and adaptive responses. In KCs, IL-33 works in an autocrine loop; it is produced by KCs following psoriatic inflammatory stimuli and induces KCs transcription of pro-inflammatory genes (CCL2, CXCL1, CXCL2, CXCL15, and vascular endothelial growth factor) [48]. Increased IL-33 serum levels have been found in patients with psoriasis, and they were significantly reduced after treatment with TNF inhibitors [30,49].  
The discovery of deficiency of IL-36 receptor antagonist (DITRA), a recessive autoimmune-flammatory syndrome due to loss-of-function mutations in the gene IL36 RN (encoding IL-36 Ra), highlighted the role of IL-36 cytokines in PP. In DITRA, unopposed signaling of IL-36 cytokines results in a severe PP phenotype with repeated flares of multiple pustules and fever, leukocytosis, and elevated serum levels of C-reactive protein [50]. Moreover, in murine and human models, KCs surrounding neutrophil pastules have shown elevated expression of IL-36 [36]. However, IL-36 cytokines are also involved in plaque psoriasis, with increased expression of IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\) in skin and serum of psoriasis patients, and a positive correlation between disease severity and cytokine levels [18,51].  
Regarding inhibitory cytokines, several studies have found decreased expression of IL-38 in both skin and blood of psoriasis patients, whereas its expression was increased in normal skin and upregulated in lesional psoriasis following treatment with anti-IL-17A biologic agents [52, 53, 54]. Lastly, IL-37 is able to inhibit IL-1\(\beta\), IL-6, TNF, and chemokines such as CCL2, all involved in psoriasis [55]. Therefore, IL-38 and IL-37 are probably also involved in the pathogenic pathways of psoriasis.