Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Mus musculus

Mammals have evolved neurophysiologic reflexes such as coughing and scratching to expel invading pathogens and noxious environmental factors. It is well established that these responses are also associated with chronic inflammatory diseases such as asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that the type 2 cytokines IL-4 and IL-13 directly stimulate sensory neurons and that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. In proof-of-concept clinical studies, we further show that patients with recalcitrant chronic itch 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, these studies reveal an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior. Overall design: RNA-sequencing of bulk ear skin from 4 adult C57Bl/6 mice treated with vehicle control (ethanol, EtOH) compared to bulk ear skin from 4 adult C57Bl/6 mice treated with 1 nmol topical calcipotriol (MC903) daily for 12 days.