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. <i>Cysltr2</i> transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected <i>CYSLTR2</i> 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 <i>Cysltr2</i> or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for <i>Cysltr1</i>, <i>Trpv1</i>, or mast cells (W^Sh 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 <i>Alternaria</i>-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and <i>Cysltr2</i>^-/- 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.