Abstract
The term psoriasis describes a phenotypically heterogeneous group of inflammatory skin disorders, associated with major co-morbidity. While progress has been made in illuminating pathways that contribute to specific disease subtypes, shared aetiological mechanisms have not been investigated. In this context, the current project sought to characterise the pathogenic role of IL-36a, -3 and -y, a group of IL-1 family cytokines involved in innate epithelial responses. The initial focus of the study was on the pathogenesis of pustular psoriasis, a rare autoinflammatory variant of the disease, associated with mutations in /L36RN and AP153. While it has been established that /L36RN defects up-regulate IL-36 signalling, the impact of AP153 disease alleles remains poorly understood. Here, the characterisation of in-vitro and ex-vivo experimental systems demonstrated that AP153 mutations disrupt keratinocyte autophagy. This causes an abnormal accumulation of the p62 NF-KB adaptor, leading to a marked up-regulation of IL-36 production and IL-1 responses. Having shown that mutations in different pustular psoriasis genes have convergent effects on IL-36 signalling de-regulation, the study sought to determine whether IL-36 cytokines also have a pathogenic role in common plaque psoriasis. The IL-36 transcriptome was first characterised in keratinocyte RNA-seq experiments. This showed a substantial overlap between the genes and pathways that are upregulated by IL-36 cytokines (e.g. IL-17 signalling and leukocyte chemotaxis) and those that are abnormally active in psoriasis. In keeping with these findings, in-vivo and ex-vivo IL-36 receptor blockade reduced IL-17 over-production and leukocyte infiltration in psoriatic skin.Finally, the deep phenotyping of human knockouts lacking a functional IL-36 receptor did not identify any anomalies in immune function, as demonstrated by the results of clinical examinations, serology tests and PBMC stimulations. This suggests that pharmacological IL-36 receptor blockade is likely to be well tolerated.
Taken together, theses data suggest that IL-36 cytokines play a key role in cutaneous inflammation by amplifying IL-17 and IL-1 signalling in keratinocytes. This highlights IL-36 inhibition as a promising therapeutic approach for the treatment of plaque and pustular forms of psoriasis.
| Date of Award | 1 Dec 2017 |
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| Original language | English |
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| Supervisor | Francesca Capon (Supervisor) & Jonathan Barker (Supervisor) |