# Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease
## 2 The Role of IL-36 Family Cytokines in Psoriasis Pathogenesis
High numbers of NETotic cells have been found in the peripheral blood of psoriasis patients, and they were correlated with disease severity [43]. The innate immune response has a predominant role in the immunopathogenesis of pustular psoriasis, with activation of the IL-1/IL-36 inflammatory axis leading to neutrophil chemotaxis and neutrophil-driven inflammatory responses [16]. Mutations in genes coding for IL-36 axis components--mainly the IL-36 RN gene but also the SERPINA3 gene--and NF\(\kappa\)B signaling pathways (CARD14, AP1S3, TNIP1) have been associated with both GPP and palmoplantar/acral pustular psoriasis [14, 44]. Moreover, findings of microarray analysis studying transcriptomes from patients with plaque psoriasis and GPP reflect this IL-1/IL-36 protagonism: expression of IL-19, IL-36\(\alpha\), IL-36\(\gamma\), and neutrophil chemokines (CXCL1, CXCL2, CXCL8) was higher, while IL-17A and IFN\(\gamma\) expression was lower in GPP lesions as compared to plaque psoriasis lesions [5]. [PERSON] and colleagues studied the role of IL-36 cytokines in linking the innate immune system activation and T-cell responses in GPP. They found a broad activation of CD4+ T-cells with increased IL-17A and TNF production in blood and skin lesions of GPP patients, as well as increased infiltration of IL-17A+ cells in skin lesions from GPP as compared to plaque psoriasis patients [45]. Immunohistochemistry studies revealed that lesional CD4+ T cells expressed IL-36R and hyperproliferated after IL-36\(\beta\) stimulation [45]. Furthermore, antigen-driven CD4+ T-cell responses were present in GPP patients irrespective of their IL-36 RN mutation status [45]. IL-36\(\alpha\) is expressed and produced by macrophages and plasma cells in the synovium of PsA patients, with expression levels similar to those in rheumatoid arthritis (RA) [46, 47]. However, [PERSON] and colleagues found a deficient expression of IL-36 Ra and IL-38 in comparison to RA, permitting an easier activation of downstream pro-inflammatory cascades by IL-36\(\alpha\) in PsA [47]. Evidence of IL-36 activation in PsA was underpinned by a higher expression of cathepsin G and neutrophil elastase in PsA [47]. In addition, the authors also found higher responsiveness of fibroblast-like synovivocytes (FLS) derived from inflamed psoriatic joints to IL-36\(\alpha\) stimulation, with higher production of IL-8 and stronger NF-\(\kappa\beta\) activation in PsA-FLS as compared to RA-FLS. TNF\(\alpha\) stimulation caused a comparable production of pro-inflammatory molecules in both disease models, suggesting a disease-dependent response specific for IL-36 [47]. IL-38 is a 17-18 kDa protein that shares 40% sequence similarity with IL-1 Ra and IL-36 Ra (antagonists of IL-1 and IL-36, respectively) and binds IL-36R to antagonize IL-36 [15]. IL-38 is expressed mostly in the skin and immune cells, and its expression is downregulated by inflammatory cytokines [28, 48]. IL-17, IL-22, and IL-36\(\gamma\) have inhibitory effects on IL-38 expression, although they induce the expression of IL-36 Ra. IL-38 has a role in KC differentiation: its expression is reduced in de-differentiated KCs, whereas terminally differentiated KCs release higher levels of IL-38 relative to IL-36 Ra [8]. IL-38 can suppress the production of IL-17A by \(\gamma\)8 T-cells through IL-1 RAcP antagonism [48].