The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.

Abstract

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2-/- mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.

• Authors: Tiphaine Voisin, Caroline Perner, Marie-Angele Messou, Stephanie Shiers, Saltanat Ualiyeva, Yoshihide Kanaoka, Theodore J Price, Caroline L Sokol, Lora G Bankova, K Frank Austen, Isaac M Chiu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 13 (03 30 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33753496 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Video-Audio Media)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• Receptors, Leukotriene
• Leukotriene C4
• cysteinyl leukotriene receptor 2

Topics

• Animals
• Chronic Disease
• Dermatitis, Atopic (chemically induced, complications, immunology, pathology)
• Disease Models, Animal
• Ganglia, Spinal (cytology, metabolism)
• Humans
• Leukotriene C4 (metabolism)
• Mice
• Mice, Knockout
• Pruritus (immunology, pathology)
• Receptors, Leukotriene (genetics, metabolism)
• Sensory Receptor Cells (metabolism)
• Signal Transduction (immunology)
• Skin (innervation, pathology)