Psoriasis is a chronic inflammatory skin disease effecting over 100,000 people in Ireland. While the hallmark of psoriasis is characterised by cutaneous inflammation and keratinocyte hyperproliferation, in recent years it has been demonstrated that dysregulated innate and adaptive immune mechanisms give rise to pathologic features in genetically prone individuals. Topicals such as corticosteroids and vitamin D analogs represent first line therapies while biologics targeting pro-inflammatory cytokines are reserved for more extensive disease. The Th17/IL-23 axis is strongly associated with psoriasis and it is now well accepted that resident immune cells become activated to produce IL-23 which then drives the production of IL-17 ligands from T cells. Together with IL-12 produced by Th1 cells, these cytokines activate the epidermis to produce further inflammatory mediators leading to a perpetual loop of inflammation. The hierarchal production of IL-17 is evidenced by the effectiveness of IL-17 blockade with biologics (currently undergoing Phase III clinical trials). There is still however a need to develop newer treatments that exhibit safer side-effect profiles. It has recently been demonstrated that Dimethylfumarate (DMF), a component of Fumaderm®, induces immunosuppression through induction of the stress response protein, heme oxygenase-1 (HO-1). HO-1 catalyses the conversion of heme to the linear tetrapyrroles (LTPs) biliverin and bilirubin with the concomitant release of carbon monoxide. These products have been shown to have immunomodulatory effects in animal models of autoimmune disease including atopic dermatitis and psoriasis. We have found that HO induction and BV treatment can directly inhibit IL-17 production in human PBMC, dendritic cells (DC) and T cells. We propose to extend our studies to examine human dermal DC, langerhan cells, keratinocytes and PBMC/skin cells from psoriatic patients. Furthermore, we have developed a method to extract naturally derived LTPs from algae which represent a safe and attractive addition/alternative to current topical and oral treatments.
