JAK2 is a key target for itch induced by AD-associated cytokines and pruritogens in human sensory neurons

Summary: Abstract Body: Atopic dermatitis (AD) is a common inflammatory skin disease associated with a type 2 immune response and intense itching. Despite the development of new therapeutic options for AD, itch in patients with AD has not yet been sufficiently alleviated. Previous studies have identified several molecular targets and genes in the itchy-sensory neurons. However, these studies have used mouse or rat nerves or their cell lines, and no research has been conducted using human nerves.In this study, we aimed to identify key molecules for itch in human sensory neurons in response to multiple pruritogens associated with AD. Cultured human iPS cell-derived sensory neurons were treated with type 2 cytokines, such as IL-4, IL-13, IL-31, and pruritogens like histamine, chloroquine, and SLIGRL-NH2. As controls for type 2 cytokines and pruritogens, the neurons were treated with IFN-γ, bradykinin, and serotonin. RNA was isolated from cells for RNA sequencing analysis. As a result, we found that JAK2 was the only elevated gene that was common to neurons treated with type 2 cytokines and pruritogens, but not to those treated with IFN-γ, bradykinin, and serotonin. This result suggests that itch mediators and AD-related cytokines activate human sensory neurons via JAK-mediated signaling pathways, especially through JAK2. Our data provide valuable insights into the molecular mechanisms of itch in AD and may help the development of treatments for itchiness. Shu Yotsumoto², Kazuhiko Yamamura^{2, 1}, Motoko Sumasu², Bing Wang², Makiko Kido-Nakahara², Gaku Tsuji^{2, 1}, Takeshi Nakahara^{2, 1} 1. Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan. 2. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Adaptive and Auto-Immunity