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

Abstract

Psoriasis is a TH17-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.

Interleukin‐17A suppresses granular layer formation in a 3‐D human epidermis model through regulation of terminal differentiation genes

“…Our research and previous studies showed that IL‐17A directly suppressed profilaggrin/FLG protein production by downregulating its mRNA expression ( FLG ) (Fig. e) . As a result, IL‐17A decreased the keratohyalin granules in the epidermal construct and induced a thin granular layer in a 3‐D epidermis model, whereas IL‐17C did not affect the structure (Fig.…”

Successful treatment of refractory juvenile generalized pustular psoriasis with secukinumab monotherapy: A case report and review of published work

“…Neutrophils in active psoriatic lesions are the largest fraction of infiltrating cells containing IL‐17, which is preformed by T‐helper 17 cells (or possibly derived from neutrophils themselves) and also highly expressed in the lesion of GPP . Previous studies indicated that psoriasis‐associated IL‐17A deregulates gene expression of IL‐36 cytokine family members in keratinocytes, which are essential for the keratinocyte feedback control, the cross‐talk between keratinocytes and neutrophils, and the influx of neutrophils into psoriatic lesions including GPP . The proteases released from the stimulated neutrophils may further activate the IL‐36 cytokines by proteolytic processing .…”

“…The proteases released from the stimulated neutrophils may further activate the IL‐36 cytokines by proteolytic processing . The DITRA due to homozygous mutations in IL36RN may enhance the inflammatory responses induced by IL‐36 cytokines, which synergize with IL‐17A and amplify the vicious cycle between keratinocytes and neutrophils in GPP …”

IL‐17A synergistically enhances TLR3‐mediated IL‐36γ production by keratinocytes: A potential role in injury‐amplified psoriatic inflammation

“…IL‐36γ is a potent inflammatory member of the IL‐1 family, produced by keratinocytes in response to multiple stimuli including cell damage . The role of IL‐36γ in psoriasis pathogenesis is increasingly recognized .…”