The CysLT(2)R receptor mediates leukotriene C(4)-driven acute and chronic itch

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 LTC(4), LTD(4), and LTE(4), are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC(4) and its signaling through the CysLT receptor 2 (CysLT(2)R) 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 C(4) (LTC(4)) or its nonhydrolyzable form NMLTC(4), but neither LTD(4) nor LTE(4), induced dose-dependent itch but not pain behaviors in mice. LTC(4)-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC(4)-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 (W(Sh) mice). CysLT(2)R 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 LTC(4) acts through CysLT(2)R as its physiological receptor to induce itch, and CysLT(2)R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.