Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

• Published in: Cell Vol. 171; no. 1; pp. 217 - 228.e13
• Main Authors: Oetjen, Landon K., Mack, Madison R., Feng, Jing, Whelan, Timothy M., Niu, Haixia, Guo, Changxiong J., Chen, Sisi, Trier, Anna M., Xu, Amy Z., Tripathi, Shivani V., Luo, Jialie, Gao, Xiaofei, Yang, Lihua, Hamilton, Samantha L., Wang, Peter L., Brestoff, Jonathan R., Council, M. Laurin, Brasington, Richard, Schaffer, András, Brombacher, Frank, Hsieh, Chyi-Song, Gereau, Robert W., Miller, Mark J., Chen, Zhou-Feng, Hu, Hongzhen, Davidson, Steve, Liu, Qin, Kim, Brian S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-09-2017
• Subjects: Animals; atopic dermatitis; Ganglia, Spinal; Humans; IL-13; IL-4; IL-4Rα; Interleukin-13 - immunology; Interleukin-4 - immunology; itch; JAK1; Janus Kinase 1 - metabolism; Mice; Mice, Inbred C57BL; pruriceptor; pruritus; Pruritus - immunology; Pruritus - metabolism; Sensory Receptor Cells - immunology; Sensory Receptor Cells - metabolism; Signal Transduction; Skin Diseases - immunology; Skin Diseases - pathology; type 2 cytokines; pruritus; itch; pruriceptor; type 2 cytokines; IL-4; atopic dermatitis; IL-13; IL-4Rα; JAK1
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.08.006

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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•Type 2 cytokines directly activate both mouse and human sensory neurons•IL-4 enhances neuronal responsiveness to multiple pruritogens•Sensory neuron-specific deletion of IL-4Rα or JAK1 reduces chronic itch•Clinical studies demonstrate that JAK inhibitors relieve chronic itch
Type 2 cytokines directly stimulate itch-sensory neurons, and blocking this pathway is effective in a proof-of-concept study in patients with recalcitrant chronic itch.