301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Abstract

Psoriasis is a T H 17-driven inflammatory disease affecting a significant proportion of the world population. The molecular consequences of IL-17 signaling in the skin are only partially understood. Therefore, we evaluated the IL-17A effects on organotypic 3-dimensional skin models and observed that IL-17A interfered with keratinocyte differentiation. In agreement with this phenotype, IL-17A repressed the expression of many genes encoding structural proteins. Moreover, genes encoding anti-microbial peptides were induced, resulting in a strengthening of the chemical barrier. Finally, we observed enhanced expression of the three IL-36 cytokines IL-36α, β and γ. We found that IL-36γ was secreted from keratinocytes in an inactive form and that neutrophilic proteases, including elastase, were capable of activating this cytokine. Functionally and similar to IL-17A, truncated IL-36 cytokines interfered with keratinocyte differentiation in 3D models. The molecular analysis revealed strong cooperative effects of IL-17A and IL-36 cytokines in regulating target genes, which was dependent on the proteolytic activation of the latter. Together these findings suggest an amplification cycle that can be initiated by IL-17A, involving IL-36 cytokines and immune cell derived proteases and resulting in active IL-36 cytokines which synergize with IL-17A. This amplification cycle might be relevant for a persistent psoriatic phenotype.Psoriasis, a chronic autoimmune disease of the skin, affects approximately 2% of the population. Psoriasis is associated with systemic inflammatory processes including inflammatory arthritis, inflammatory bowel disease, and metabolic syndrome 1,2 . A typical manifestation of the disease is the hyperproliferation of keratinocytes with premature differentiation. This results in incomplete cornification with retention of nuclei in the stratum corneum, referred to as parakeratosis. Functionally this correlates with increased infiltrations of immune cells due to dendritic cells, macrophages, neutrophils and different subpopulations of T cells. These cells modify the cytokine milieu and thus affect the behavior of keratinocytes resulting in altered differentiation [1][2][3]

Long-Term and Clinically Relevant Full-Thickness Human Skin Equivalent for Psoriasis

“…In the collagen models, fibroblasts are embedded in collagen I gels, which function as dermal equivalents. 16 Collagen models can demonstrate characteristic psoriatic phenotypes like epidermal hyperplasia and hypogranulosis and express typical disease markers like HBD-2, SKALP/elafin, and/or S100A7, 4 , 17 but these models suffer from poor mechanical strength, contraction, and a limited life span. 18 Typically, these full-thickness skin models start to degrade after approximately 14 days.…”

“…Over the years, many in vitro models of psoriasis are developed to study the pathogenesis of psoriasis and to explore for new therapeutic drug candidates. − Currently, the cytokine stimulation approach for developing disease pathogenesis is mainly applied to collagen-based full-thickness skin models. In the collagen models, fibroblasts are embedded in collagen I gels, which function as dermal equivalents . Collagen models can demonstrate characteristic psoriatic phenotypes like epidermal hyperplasia and hypogranulosis and express typical disease markers like HBD-2, SKALP/elafin, and/or S100A7, , but these models suffer from poor mechanical strength, contraction, and a limited life span .…”