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Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk
Luigi Tortola, … , Jan Kisielow, Manfred Kopf
Luigi Tortola, … , Jan Kisielow, Manfred Kopf
Published October 15, 2012
Citation Information: J Clin Invest. 2012;122(11):3965-3976. https://doi.org/10.1172/JCI63451.
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Research Article Dermatology

Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk

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Abstract

Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world’s population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R–deficient (Il36r–/–) mice were protected from imiquimod-induced expansion of dermal IL-17–producing γδ T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn–/–) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36–mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r–/– mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1–independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.

Authors

Luigi Tortola, Esther Rosenwald, Brian Abel, Hal Blumberg, Matthias Schäfer, Anthony J. Coyle, Jean-Christoph Renauld, Sabine Werner, Jan Kisielow, Manfred Kopf

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Figure 1

IL-36R and IL-36R antagonist play critical roles in the development of IMQ-induced psoriasiform dermatitis.

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IL-36R and IL-36R antagonist play critical roles in the development of I...
Ears of both Il36r–/– and Il36rn–/– mice and WT mice (n ≥ 4 per group) were topically treated with an IMQ-containing cream (Aldara, MEDA Pharma) for 7 consecutive days. (A) Ear swelling was measured daily before treatment. Values show averages ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. (B) At day 7, photographs were taken from whole ears or (C) H&E-stained ear sections representing the thickest epidermal region of each ear from individual mice representative of indicated groups. Epidermis (e), dermis (d), and hair follicle (f) are indicated. Data are representative of 4 experiments. Scale bar: 100 μm.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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