The CysLT ₂ R receptor mediates leukotriene C ₄ -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.

Interactions of the Neuro‒Immune‒Stromal Triad in Itch

“…Release of agents from mast cells elicits pruritus by direct activation of itch neurons, and they express all the biosynthetic apparatus to achieve this (Figure 1e) (Buhl et al, 2020;Reddy et al, 2015;Solinski et al, 2019b;Voisin et al, 2021). These agents include histamine, serotonin, leukotrienes, and sphingosine-1-phosphate (Stone et al, 2010) (Figure 1e).…”

Connections between Immune-Derived Mediators and Sensory Nerves for Itch Sensation

“…NP1 expresses the β-alanine receptor Mrgprd [10] and the lysophosphatidic acid receptors Lpar3 and Lpar5. Chloroquine (CQ) receptor (Mrgpra3) and bovine adrenal medulla (BAM) 8-22 receptor (Mrgprx1:human, Mrgprc11:mice) [11] are expressed on NP2; whereas the interleukin (IL)-31 receptor Il31ra, the oncostatin M receptor (OSM), the leukotriene (LT) C 4 receptor Cysltr2 [12] and the serotonin receptors Htr1f and Htr2a are expressed on NP3. Histamine receptor (H1R) was detected on NP2 and NP3 [9] (Figure 1).…”

“…LTC 4 is a cysteinyl LT produced and released by mast cells, basophils, and eosinophils [131][132][133]. Its receptors, CysLTR1 and CysLTR2, are widely expressed by hematopoietic and structural cells [12]. Basophils have been shown to release LTC 4 upon stimulation with antigen-specific IgE, which binds to CysLTR2 expressed on sensory nerve fibers (mainly NP3 nerves), evoking acute severe itch (itch flares) of AD [132].…”

“…Basophils have been shown to release LTC 4 upon stimulation with antigen-specific IgE, which binds to CysLTR2 expressed on sensory nerve fibers (mainly NP3 nerves), evoking acute severe itch (itch flares) of AD [132]. Moreover, the LTC4/CysLTR2 pathway was shown to contribute not only to acute but also to chronic itch [12].…”

Itch in Hymenoptera Sting Reactions

“…Tryptase has been shown to activate proteaseactivated receptor 2 (PAR-2), which can cause itch flares in patients with atopic dermatitis. LTC 4 can mediate itch through the cysteinyl leukotriene receptor 2 (CysLTR2) on sensory nerves (43,44).…”