PracticeUpdate: Dermatology - Winter 2018

CONFERENCE COVERAGE 30

Neutralization of Interleukin 17 Implicated in Inflammatory Skin Diseases Overall and in Psoriasis Specifically Interleukin 17C was explored as a checkpoint in innate skin immunology, and interleukin 17A in terms of molecular transformation. These two presentations were delivered IID 2018.

activation of NFкB, and forms a pro-inflammatory feedback loop with TNFα. Dr. Lauffer concluded, “We were able to demonstrate that interleu- kin 17C potentiates the inflammatory response of keratinocytes in vitro and that specific neutralization of interleukin 17C decreases inflammation in murine and human models of psoriasis and atopic dermatitis. Inhibition of interleukin 17C signaling is a promising, novel approach to treat inflammatory skin diseases.” Molecular transformation during interleukin 17A treatment T rine Bertelsen, MD, of Aarhus University in Denmark, explained that antagonists of interleukin 17 have proven to be highly effective for psoriasis. Many mechanisms under- lying this efficacy, however, have yet to be determined. Moreover, mechanisms underlying molecular remission of psoriasis remain elusive.

Interleukin 17C: A checkpoint in innate skin immunology F elix Lauffer, MD, of the Technische Universität München in Munich, Germany, explained that inflammatory skin diseases are frequent and exert a major impact on quality of life. While the importance of interleukin 17A is well known, other members of the interleukin 17 family, such as interleukin 17C, remain poorly investigated.

Dr. Lauffer told Elsevier’s PracticeUpdate , “Inflammatory skin disease are frequent and impact quality of life severely. While new ther- apeutic strategies for psoriasis have been discovered with great success, targeted ther- apies in other inflammatory skin diseases, such as atopic dermatitis, are still needed. We performed this study to understand how the epithelial- derived cytokine interleukin 17C can

Dr. Felix Lauffer

Dr. Bertelsen and colleagues set out to inves- tigate molecular complexity in psoriatic patients during treatment with an anti-interleu- kin 17A agent. Fourteen patients treated with secukinumab (anti-interleukin 17A) were included. Skin biop- sies and blood samples were collected at day 0, 4, 14, 42, and 84. Clinical scores such as Psoriasis Affected

influence skin inflammation.” Dr. Lauffer and colleagues detected high numbers of interleukin 17C-positive cells in diverse inflammatory, autoimmune, and infec- tious skin diseases. In keratinocytes, interleukin 17C was induced by interleukin 1β, flagellin, and tumor necrosis factor α (TNFα) via upregulation of p65, phospho-p65, and IкBα. Expression of interleukin 17C transcripts was dependent on NFкB and ERK1/2. Stimulation of interleukin 17C led to enhanced expres- sion of antimicrobial peptides in primary human keratinocytes. This effect was potentiated synergistically by costimulation with TNFα. Cell-free supernatant of keratinocytes stimulated with interleukin 17C enhanced the migratory potential of neutrophil granulocytes to a comparable level as CXCL8. To assess the relevance of interleukin 17C in a complex model of human disease, Dr. Lauffer’s team finally cultured human skin biopsies of psoriasis and atopic dermatitis with an interleukin 17C-neutralizing antibody. Compared with untreated controls, neutralization of interleukin 17C led to significant downregulation of pro-inflammatory cytokines and antimicrobial peptides, for example, interleukin 36G (DEFB4A). This downregulation demonstrated the crucial role of interleukin 17C in human inflammatory conditions. Dr. Lauffer concluded that interleukin 17C is broadly expressed in human skin pathology, is induced by innate immune stimulative

Dr. Trine Bertelsen

Surface Area, Physician's Global Assessment, and body surface area were registered at each visit. Samples were then pro- cessed for microarray, quantitative polymerase chain reaction, and immunohistochemistry. Inflammatory mediators such as CXCL8, interleukin 19, DEFB4, and interleukin 36A were downregulated early, at day 4 after the start of treatment. Other mediators such as S100A7, interleukin 20, and CCL20 were downregulated at day 14. Moreover, when comparing nonlesional skin with previous lesional skin at day 84, expression of several molecular markers was altered, even though psoriasis had cleared. IкBζ, encoded by the NFKBIZ gene, is a key regulator in psoriasis through its role in mediating interleukin 17A-driven effects. Inter- estingly, NFKBIZ mRNA expression was downregulated during anti-interleukin 17A treatment and correlated with clinical scores. Therefore, signaling pathways involved in interleukin 17A-induced IкBζ expression were investigated further in human keratinocytes. By using siRNA knockdown and quantitative polymerase chain reaction, Dr. Bertelsen’s team demonstrated IкBζ to be mediated through an Act1/p38 MAPK/c-Jun/NF-кB- dependent mechanism. Dr. Bertelsen concluded that the results provided insight into molecular transformation during anti-interleukin 17A treatment. They provide an explanation of the molecular “scar” that is gen- erated when psoriasis is in remission. Furthermore, the results presented IкBζ as an important player in interleukin 17A-driven effects in psoriasis. www.practiceupdate.com/c/68290

" …the results provided insight into molecular transformation during anti-interleukin 17A treatment. They provide an explanation of the molecular “scar” that is generated when psoriasis is in remission. "

PRACTICEUPDATE DERMATOLOGY