Researchers with the PSORIASIS IL17 (Investigating the role of dysregulated interleukin-17 signalling in the pathogenesis of psoriasis) project investigated how interleukin-17 (IL-17) activates other molecules to trigger inflammatory response and psoriasis. IL-17 cytokines are important in immune responses to bacteria and fungi. Moreover, in trials, an anti-IL-17 that targets IL-17A has successfully treated psoriasis but is prohibitively expensive for most patients. Looking for other signalling pathways initiated by IL-17 cytokines that play a role in inflammatory diseases such as psoriasis, the researchers selected two candidates, IL-17 receptor D (IL-17RD) and IL-17C. IL-17RD reduces immune responses triggered by IL-17A and, using transgenic mice, the team observed a protective role for IL-17RD in psoriasis. Expression of the receptor in diseased tissue was accompanied by an increase in pro-inflammatory molecules. Moreover, IL-17RD has a ligand that activates macrophages to counteract inflammation. Activating a chemical pathway compared with blocking inflammatory response is an attractive therapeutic option. Applying chemical and mechanical stress to keratinocytes, the PSORIASIS IL17 project observed an increase in expression of IL-17C that in turn led to increased production of pro-inflammatory cytokines. The researchers identified a new IL-17C target, a protein encoded by a gene previously found in psoriasis patients. Using in vitro studies, they identified key transcription factors produced in these mutant cells that activate pro-inflammatory cytokine and chemokine responses. The work on IL-17C sheds light on the initiation phase of psoriasis and mirrors the so-called Koebner phenomenon in patients whereby a scratch on unaffected skin produces a lesion. Furthermore, implications of the chemokine responses are that the pro-inflammatory response may be perpetuated as chemokines chemically attract certain types of immune cell. PSORIASIS IL17 research deliverables have made many steps towards development of pharmaceutical leads for psoriasis in the European Research Area (ERA). The newly developed mouse model will serve as a useful tool in future research. New therapeutics will mean fewer hospital consultations and a corresponding decrease in lost working hours within Europe’s workforce.
Psoriasis, PSORIASIS IL17, cytokines, IL-17RD, IL-17C