A Targetable, Noncanonical Signal Transducer and Activator of Transcription 3 Activation Induced by the Y-Less Region of IL-22 Receptor Orchestrates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.

Abstract

Exacerbated IL-22 activity induces tissue inflammation and immune disorders such as psoriasis. However, because IL-22 is also essential for tissue repair and defense at barrier interfaces, targeting IL-22 activity to treat psoriasis bears the risk of deleterious effects at mucosal sites such as the gut. We previously showed in vitro that IL-22 signaling relies on IL-22 receptor alpha (IL-22Rα) Y-dependent and -independent pathways. The second depends on the C-terminal Y-less region of IL-22Rα and leads to a massive signal transducer and activator of transcription 3 (STAT3) activation. Because STAT3 activation is associated with the development of psoriasis, we hypothesized that the specific inhibition of the noncanonical STAT3 activation by the Y-less region of IL-22Rα could reduce psoriasis-like disease while leaving intact its tissue defense functions in the gut. We show that mice expressing a C-terminally truncated version of IL-22Rα (ΔCtermut/mut mice) are protected from the development of psoriasis-like dermatitis lesions induced by imiquimod to a lesser extent than Il22ra-/- mice. In contrast, only Il22ra-/- mice lose weight after Citrobacter rodentium infection. Altogether, our data suggest that specific targeting of the noncanonical STAT3 activation by IL-22 could serve to treat psoriasis-like skin inflammation without affecting IL-22‒dependent tissue repair or barrier defense at other sites.

• Authors: Camille Michiels, Léna Puigdevall, Perrine Cochez, Younes Achouri, Paméla Cheou, Emilie Hendrickx, Nicolas Dauguet, Christophe Blanchetot, Laure Dumoutier
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 11 Pg. 2668-2678.e6 (11 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 33992648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukins
• Receptors, Interleukin
• STAT3 Transcription Factor
• Stat3 protein, mouse
• interleukin-22 receptor
• Imiquimod
• interleukin-22

Topics

• Animals
• Citrobacter rodentium
• Enterobacteriaceae Infections (immunology)
• Imiquimod (toxicity)
• Interleukins (pharmacology)
• Mice
• Mice, Inbred C57BL
• Psoriasis (chemically induced)
• Receptors, Interleukin (physiology)
• STAT3 Transcription Factor (physiology)