Defining a PGE2 Pathway in Regulating Eczema

Defining a specific IL-22-mediated pathway in regulating eczema (i) Introduction: Overarching aim: Eczema is a significant chronic skin disease yet the need for targeted treatments remains largely unmet. In this study, I will investigate the cellular mechanisms for how the IL-22 pathway contributes to skin inflammation in eczema and whether pharmacologic manipulation of this pathway might offer effective new treatments for this common disease.

Main hypothesis and objectives: I hypothesise that prostaglandin E2 (PGE2) promotes eczema through activating IL-22 signalling and that blockade of PGE2 receptors EP2/EP4 reduces eczema severity. I will interrogate this hypothesis with three objectives: (1) to examine whether IL22 overexpression in eczema patients is driven by endogenous PGE2 acting via EP2 and EP4 receptors, (2) to determine whether this PGE2-IL-22 pathway is of particular importance in distinct subtypes of eczema and, (3) to study whether blocking EP2/EP4 receptors upstream of IL-22 and IL-17 will reduce eczema severity.

Background and importance of research:

Eczema is the most common chronic inflammatory skin disease, with a rising prevalence in Western society placing an increasing economic burden on the health service.3 It is increasingly being recognised as a heterogenous disease encompassing acute and chronic eczema, and allergic contact dermatitis (ACD). It cumulatively affects over 4% of adults and 10% of children of whom 50% have persistent disease in adulthood. The recent UK Translational Research Network in Dermatology priority setting exercise highlighted the burden created by this common and important disease.The requirement for a greater understanding of eczema pathogenesis according to subtype allowing patient stratification, and the dearth of treatment options available are significant unmet needs. This is in contrast with advances made in the development of biological therapies for psoriasis although refinement of these was also prioritised.

Atopic eczema may predispose children to the "atopic march", and early effective treatment may reduce progression to asthma and hayfever in these patients. Understanding the immune pathway in eczema may provide insight into inflammatory pathways generic to a range of diseases especially those arising at the environmental allergen/epithelial interface.