Abstract
Interleukin 36α, -β and –γ (hence IL-36) are a group of innate cytokines that play a key role in epithelial immune homeostasis. In fact, mutations causing excessive IL-36 signalling have been associated with generalised pustular psoriasis (GPP), a severe autoinflammatory disease presenting with flares of skin pustulation and systemic upset.Given that GPP patients often suffer from concurrent plaque psoriasis (Ps), the hypothesis underlying this study was that abnormal IL-36 activity may also contribute to the pathogenesis of Ps. As the disease presents with cutaneous (red, scaly plaques) and systemic (increased cardiovascular risk) manifestations, the effects of IL-36 were examined in both contexts.
In the first part of the research, a signature of IL-36 activation was defined through the transcription profiling of primary keratinocytes treated with IL-36α, -β or γ. This identified a core set of transcripts that are up-regulated by all three cytokines. Importantly, these differentially expressed genes (DEG) showed an enrichment for pathways related to IL-17 signalling and leukocyte chemotaxis, two processes that are critical to the pathogenesis of Ps. There was also a marked overlap between the genes that are up-regulated by IL-36 and those that are over-expressed in Ps skin.
The second part of the study focused on the systemic effects of IL-36. These were initially investigated by whole-blood RNA-sequencing of GPP cases and unaffected controls. While the experiment confirmed the up-regulation of IL-36 dependent transcripts in GPP, it also showed an unexpected over-expression of Type-I IFN stimulated genes. Signatures of abnormal IL-36 and Type-I IFN activity were also observed in Ps leukocytes. Follow-up experiments demonstrated that IL-36 acts directly on plasmacytoid dendritic cells, where it up-regulates Toll-like receptor-9 signalling and IFN-α production. 13 Taken together, these findings demonstrate that IL-36 plays an important role in the cutaneous and systemic pathogenesis of Ps.
| Date of Award | 17 Jul 2019 |
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| Original language | English |
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| Supervisor | Francesca Capon (Supervisor), Francesca Ciccarelli (Supervisor), Jonathan Barker (Supervisor) & Catherine Smith (Supervisor) |