## 3 Expression and Role of IL-36 Cytokines in Inflamed Skin and Joints
### Expression and Role in the Inflamed Joints  
In the synovial tissue of RA patients, IL-36 cytokines are expressed by various cells: plasma cells, macrophages and, to a lower extent, fibroblasts, endothelial cells, and dendritic cells [40; 64]. During the course of collagen-induced arthritis (CIA) in mice, the gene expression of IL-36\(\alpha\), -\(\beta\), and -\(\gamma\), and IL-36 Ra is locally enhanced in the joints at the peak of inflammation [40]. Fibroblast-like synoviocytes (FLS) from RA synovial membranes express IL-36R, and, upon IL-36 stimulation, they proliferate and produce proinflammatory cytokines, chemokines, and MMPs [65; 66]. Besides, IL-36 cytokines have recently been demonstrated to mediate the cross-talk between plasma cells and FLS within the inflamed joints, eventually supporting the maintenance of autoreactive B cell niches [66].  
Approximately 40% of subjects with RA are characterized by synovial ectopic lymphoid structures (ELS) surrounded by plasma cells, which locally produce pathogenic autoantibodies and may influence the chronicity of the inflammatory response [67]. Interestingly, IL-36 is also associated with the presence of ELS in other organs and diseases, e.g., colorectal cancer [68]. A role for IL-36 in inducing and maintaining ELS formation in RA synovium is therefore plausible and potentially exploitable for therapeutic purposes.  
Furthermore, IL-36\(\gamma\) can promote T cell differentiation towards IL-9-producing lymphocytes (Th9) [69], which have been associated with augmented neutrophils survival and enhanced Th17 differentiation in the synovial tissue [70]. Not surprisingly, Th9 cells are enriched in peripheral blood and synovium of patients with inflammatory arthritis [71; 72], and their presence correlates with disease activity in RA [70].  
Although IL-36 cytokines are widely expressed within the synovial tissue, they seem to be generally dispensable for driving local and systemic inflammation in autoimmune arthritis. The silencing of IL-36R with blocking antibodies or by inhibiting its gene expression does not affect inflammation and bone destruction in several experimental models of arthritis [73; 74; 75], differently from that observed in models of psoriasis. However, it has been described that a subset of RA patients (-20%) is characterized by an elevated agonists (IL-36\(\alpha\), \(\beta\), and \(\gamma\))/antagonists (IL-36 Ra and IL-38) ratio, as found in more than 90% of patients with psoriasis [40].  
The presence of different subgroups of RA patients could be explained by the considerable heterogeneity of the human synovial tissue during inflammatory joint diseases [76]. It is plausible, therefore, that the subpopulation of RA patients with an increased IL-36 agonists/antagonists ratio has a peculiar synovial histological pathotype and/or a specific clinical phenotype. Since the histological and clinical features of this group of patients who could potentially benefit from IL-36 inhibition have not been defined yet, further research in this field will be critically important, particularly in keeping with the still significant rate of non-responders to the currently available treatment.  
In line with the importance of IL-36 cytokines in driving skin psoriasis and the recognized role played by Th17-related cytokines in the development of PsA [5], we hypothesized that the IL-36 axis could be actively involved in driving synovial inflammation in PsA. The available knowledge on this topic is relatively little and, so far, a single study has confirmed the expression of IL-36\(\alpha\) in PsA synovium [64]. Our data (unpublished, manuscript in preparation) reinforce this concept but also further suggest that the impaired balance between IL-36 agonists and antagonists contributes to the persistent inflammatory response that characterizes the inflamed synovium.  
The main functions exerted by IL-36 agonists on inflammatory cells involved in skin and joint inflammation are represented in Figure 2.