# The Significance of IL-36 Hyperactivation and IL-36R Targeting in Soriasis
## 6 Therapeutic Potential of IL36R-Targeting in Psoriasis  
Psoriasis is a complex and heterogeneous inflammatory skin disease, which can manifest as different clinical forms, characterized by distinct genetic backgrounds and inflammatory signatures [64]. Pustular psoriasis, including GPP and PPP, is commonly characterized by innate immune responses typical of acute skin lesions of plaque psoriasis, where IL-1/IL-36 inflammatory axis plays a pathogenic role in the recruitment and activation of neutrophils [24]. In contrast, chronic plaque psoriasis is mainly characterized by adaptive Th17/Th1 immune responses, in which the inflammatory cytokines IL-17A and IFN-\(\gamma\) predominate.  
Several studies reported that serum and skin levels of IL-36\(\gamma\) are elevated in patients with psoriasis and are closely associated with disease activity [13; 16; 65]. Concomitantly to the increased levels of IL-36\(\gamma\), IL-38 levels strongly drop in patients affected by plaque psoriasis, thus altering the pro-inflammatory/anti-inflammatory balance of IL-36 [13]. To date, data on IL-38 expression in other clinical subtypes, such as GPP and PPP, are lacking. Importantly, the significance of the pathogenic role of IL-36 in psoriasis is supported by the observation that the therapeutic efficacy of topical or systemic drugs used for psoriasis treatment positively correlates with a reduction of circulating and skin levels of the pro-inflammatory IL-36 agonists [16; 66] and an increase of the anti-inflammatory IL-38 antagonist [13].  
These findings, together with the genetic studies in psoriatic patients, encouraged the employment of IL-36R blocking antibodies in clinical trials. Currently, ANB019 is under phase II study for GPP and PPP treatment. As additional strategies to suppress IL-36 activity, small molecules inhibiting the elastases responsible for the maturation of IL-36 agonists have been recently developed and tested in preclinical models of psoriasis [67].  
Due to its anti-inflammatory and anti-angiogenic properties, the therapeutic use of IL-38 cytokine might represent an alternative approach to block IL-36R activation in psoriasis and in other IL-17/IL-36-dependent inflammatory diseases. In support of this hypothesis, the administration of a recombinant full-length form of IL-38 attenuates the severity of the disease in the IMQ-induced murine model of psoriasis, by reducing the local inflammation and restoring the epidermal differentiation [13]. Consistently, a mature variant of IL-38 also ameliorated the psoriasisiform phenotype induced by IMQ and this effect was more pronounced in IL38 \(\text{KO}^{\gamma/\gamma}\) mice compared to wild-type counterparts. These data suggest that a potential therapy with exogenous IL-38 could be addressed to the inflammatory diseases characterized by low levels of endogenous IL-38, such as plaque psoriasis [38]. Interestingly, IL-38 has the peculiarity to target more than one receptor of the IL-1 family and to interfere with more than one cytokine, including IL-17, IL-36, and TNF-\(\alpha\)[31]. IL-38 is also able to inhibit TLR4 signaling and to reduce indirectly the release of IL-36\(\gamma\), as well as the production of IL-6 and IL-23 by human macrophages [68].  
Due to the broad range of receptors, potentially targeted by IL-38 and differently activated during the course of psoriasis, IL-38 manipulation could represent a valid therapeutic strategy for the treatment of acute and chronic psoriatic skin lesions, as well as of other disease subtypes. Importantly, this peculiarity of IL-38 could circumvent inherent drawbacks of the current biological drugs, targeting TNF-\(\alpha\) or IL-17 cytokines, such as immune mechanisms of redundancy and compensation, which can lead to therapy resistance or adverse reactions, as described for anti-TNF-\(\alpha\) or anti-IL-17A drugs [69].