# The Significance of IL-36 Hyperactivation and IL-36R Targeting in Soriasis
## 5 Impact of IL-36R Manipulation in Preclinical Models of Skin Inflammation  
The impact of the manipulation of IL-36 axis has been widely investigated in several experimental models of psoriasis. Mice deficient of IL-36R or treated with IL-36R blocking antibodies are protected from skin inflammation induced by IMQ, an activator of TLR7 able to induce the pro-inflammatory IL-23/IL-17 axis [58; 59]. Similarly, a xenograft model of psoriasis treated with an anti-human IL-36R antibody showed a significant reduction of epidermal thickness and inflammatory immune infiltrate [30]. IL-36R antagonistic antibodies inhibit inflammatory responses also in other preclinical models of psoriasisiform dermatitis, such as in murine models of IL-23 or IL-36\(\alpha\) ear-injection, which recapitulate some of key features of psoriatic skin lesions, including leucocyte infiltration and acanthosis. In these models, the inhibition of IL-36 pathway results in a significant attenuation of skin thickening and psoriasis-relevant gene expression [60]. On the other hand, IL-36 Ra antagonist-deficient mice show exacerbated IMQ-induced psoriasisiform phenotype [59]. Among IL-36 agonists, IL-36\(\alpha\) is essential for the development of murine psoriasis [61]. In fact, transgenic mice overexpressing IL-36\(\alpha\) in keratinocytes show a transient but severe skin inflammation at birth, which waned after 2-3 weeks of age. This inflammatory skin phenotype was aggravated by IL-36 Ra deletion [62]. _Vice versa_, IL-36\(\alpha\) deletion results in the amelioration of IMQ-induced skin lesions, with the reduction of epidermal neutrophils and keratinocyte acanthosis, while the specific deficiency of IL-36\(\beta\) or IL-36\(\gamma\) does not affect the disease severity [63].  
Overall, IL-36 receptor inhibition could represent a promising therapeutic strategy for treating psoriasis, especially the pustular forms, in which the hyperactivation of IL-36 axis contributes to the repeated recruitment and activation of neutrophils.  
\begin{table}
\begin{tabular}{c c c c c} \hline
**IL-36 Members** & **Expression** & **Induction** & **Dow-Regulation** & **Refs** \\ \hline \multirow{2}{*}{IL-36\(\alpha\) (IL-1F6)} & Keratinocytes, endothelial cells, macrophages, dendritic cells, Langerhans cells & IL-17A, TNF-\(\alpha\), IL-22 & [13; 17; 18; 49] \\ \hline \multirow{2}{*}{IL-36\(\beta\) (IL-1F8)} & \multirow{2}{*}{Endothelial cells} & IL-36\(\beta\), IL-17A, TNF-\(\alpha\), IL-22, IL-1\(\beta\), LPS & [13; 17; 18; 49] \\ \hline \multirow{2}{*}{IL-36\(\gamma\) (IL-1F9)} & Keratinocytes, endothelial cells, macrophages, dendritic cells, Langerhans cells & IL-17A, TNF-\(\alpha\), IL-36\(\gamma\), IL-36\(\gamma\), NETs & [13; 17; 18; 49; 50] \\ \hline \multirow{2}{*}{IL-36 Ra (IL-1F10)} & \multirow{2}{*}{Keratinocytes} & IL-17A, TNF-\(\alpha\), IL-36\(\gamma\) & \multirow{2}{*}{[13; 17; 18; 49]} \\ \cline{1-1} \cline{5-5}  & & IL-36\(\gamma\) & IL-17A, TNF-\(\alpha\), IL-22, IL-36\(\gamma\), IFN-\(\gamma\) & [13; 34] \\ \hline \multirow{2}{*}{IL-36R complex} & Keratinocyte, fibroblasts, endothelial cells, macrophages, dendritic cells, Langerhans cells & & \\ \hline \end{tabular}
\end{table}
Table 1: Expression of IL-36 members and IL-36R complex in skin resident and immune cells present in psoriatic skin lesions.