## 4 II-37 and IL-38, Broad Inhibitors of Skin and Joint Inflammation
### Anti-Inflammatory Role of IL-38 in Skin and Joints  
The IL-38 gene expression profile in skin and joints is the opposite of the IL-36 agonists and IL-36 Ra, with IL-38 mRNA being significantly reduced in the inflamed skin [40]. In addition, during the course of CIA in mice, IL-38 articular expression is increased lately in the resolution phase of inflammation in comparison with IL-36/IL-36 Ra that are induced at the peak [40]. It is plausible to hypothesize that the lack of IL-38 may contribute to the persistent chronic inflammatory response characterizing psoriasis, RA, or PsA. Alike IL-37, IL-38 has been shown to globally reduce the IL-1-, IL-36-, and TLR-mediated inflammation but with different mechanisms. IL-38 can act \"directly\" on the IL-36 axis by binding IL-36R (as IL-36 Ra). Instead, IL-37 cannot directly modulate the IL-36 cytokines but it exerts its effect via IL-1R8. Thanks to the \"direct\" mechanism, IL-38 can decrease the IL-36-dependent IL-8 expression by human PBMCs [33] and inhibit the phosphorylation of MAPK/NFxB induced by IL-36\(\gamma\) in  
Figure 3: Main activities of IL-37 and IL-38 on skin and joints inflammation in mice and human. CIA = Collagen-Induced Arthritis; SCW = Streptococcal Cell Wall; PBMC = Peripheral Blood Mononuclear cells; RA = Rheumatoid Arthritis; STIA = Serum Transfer Induced Arthritis; Th = T helper; PsA = Psoriatic Arthritis. keratinocytes. In this way, IL-38 counteracts the proinflammatory activities played by IL-36 agonists on keratinocytes [94]. Consistently, the administration of IL-38 reduces the endogenous level of IL-36\(\gamma\) within the inflamed skin in mice [94]. The inhibitory action of IL-38 on the IL-36 pathway can also be 'indirect' through at least two additional mechanisms. On the one hand, since IL-36\(\gamma\) expression is enhanced by TLR4 activation, the IL-38-mediated inhibition of TLR signaling indirectly decreases the release of the agonist IL-36\(\gamma\)[39]. For instance, IL-38 reduces TLR4-mediated inflammation by significantly decreasing IL-6 and IL-23 produced by THP1 cells or primary M1 macrophages upon LPS stimulation [95,96]. Since blocking the TLR4 pathway in an animal model of DITRA syndrome significantly limits the auto-inflammatory response [97], the IL-38-mediated targeting of the TLR signaling in inflammatory skin conditions is encouraging. On the other hand, the downregulation of Th17-associated mediators operated by IL-38 has rebound effects on IL-36, which is a potent inducer of IL-23 [54] and can feedback positively the loop with the Th17 cytokines. In fact, PBMCs treated in vitro with a combination of IL-38-siRNA and TLR-ligands produce more mediators involved in Th17 cells recruitment and activation (e.g., IL-6 or CCL2) [98]. The low endogenous levels of IL-38 [94,94] are not able to control the course of imqiumod-induced psoriasis in mice [99]; however, the exogenous administration of recombinant IL-38 attenuates the severity of the disease [94]. The supplementation of IL-38 is also able to improve the skin lesions in an animal model of systemic lupus erythematosus [100]. Concerning the effects of IL-38 on arthritis, the induction of serum-transfer induced arthritis (STIA) in IL-38-deficient mice determines a more severe phenotype and a higher joint expression of IL-1\(\beta\) and IL-6 compared with littermates control [101]. Accordingly, the overexpression of IL-38 in the joints of CIA and STIA mice can reduce Th17 cytokines production and improve the clinical scores of the disease [96]. As observed for IL-37, IL-38 expression in plasma, synovial fluid, and synovium of RA patients is higher in comparison with healthy or OA controls, and correlates with disease activity [102, 40], thus suggesting its potential use as a diagnostic or prognostic biomarker in RA. In psoriatic patients, instead, IL-38 levels are reduced in both plasma and affected skin [94, 40], and the ratio between IL-36\(\gamma\) and IL-38 expression associates with disease activity.