Journal Club-2021.04.09

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

ABSTRACT

Acute and chronic itch are burdensome manifestations of skinpathologies including allergic skin diseases and atopic dermatitis,but the underlying molecular mechanisms are not well understood.Cysteinyl leukotrienes (CysLTs), comprising LTC4,LTD4, and LTE4,areproduced by immune cells during type 2 inflammation. Here, weuncover a role for LTC4and its signaling through the CysLT receptor2 (CysLT2R) in itch.Cysltr2transcript is highly expressed in dorsalroot ganglia (DRG) neurons linked to itch in mice. We also detectedCYSLTR2in a broad population of human DRG neurons. Injection ofleukotriene C4(LTC4) or its nonhydrolyzable form NMLTC4,butnei-ther LTD4nor LTE4, induced dose-dependent itch but not pain be-haviors in mice. LTC4-mediated itch differed in bout duration andkinetics from pruritogens histamine, compound 48/80, and chloro-quine. NMLTC4-induced itch was abrogated in mice deficient forCysltr2or when deficiency was restricted to radioresistant cells. Itchwas unaffected in mice deficient forCysltr1,Trpv1, or mast cells(WShmice). CysLT2R played a role in itch in the MC903 mouse modelof chronic itch and dermatitis, but not in models of dry skin or com-pound 48/80- orAlternaria-induced itch. In MC903-treated mice,CysLT levels increased in skin over time, andCysltr2−/−mice showeddecreased itch in the chronic phase of inflammation. Collectively,our study reveals that LTC4acts through CysLT2R as its physiologicalreceptor to induce itch, and CysLT2R contributes to itch in a model ofdermatitis. Therefore, targeting CysLT signaling may be a promisingapproach to treat inflammatory itch.

Keywords: itch, neuroimmune, atopic dermatitis, skin, inflammation