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

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 3

IL-36R on radioresistant resident cells is crucial for the expression of IL-17A in the skin and development of IMQ-induced skin inflammation.

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IL-36R on radioresistant resident cells is crucial for the expression of...
Reconstituted bone marrow chimeras, Il36r–/– CD45.2 BM → WT CD45.1 mice (KO→WT), WT CD45.1 BM → Il36r–/– CD45.2 mice (WT→KO), and WT CD45.1 BM → WT CD45.1 mice (WT→WT), were treated with Aldara cream, as described in the legend to Figure 1. (A) Ear thickness was monitored daily. (B–F) At day 7, cell populations in the ear were characterized by flow cytometry. Total numbers of (B) CD45+ hematopoietic cells and neutrophils, (C) γδ and αβ T cells, and (D) IL-17A–producing cells in ears of indicated chimeras are shown. (E) Characterization of IL-17A+ cells. (F) Percentage of host-derived remaining hematopoietic cell populations that survived the irradiation and were not replaced. (A–C, E, and F) Values indicate averages ± SEM of groups. (D) Symbols represent individual mice, and horizontal lines indicate averages of groups. *P < 0.05; **P < 0.01.