LAUSR

Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3+ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle. Description A pathologic miswiring in the epithelial touch receptor results in adaptive activation of sensory pruriceptor to propagate the itch-scratch cycle. (Don’t) scratch the itch Scratching can temporarily suppress itch sensation. However, persistent scratching can have worsening effects on itch, by triggering the so-called itch-scratch cycle. The mechanisms responsible for this pruritogenic effect remain to be elucidated. Here, Feng et al. showed that the Piezo2 channels in Merkel cells are responsible for the itch triggered by mechanical stimulation in dry skin. In dry, itchy skin, the authors noted a miswiring of nerve endings toward Merkel cells that was absent in normal skin, suggesting that wiring alterations and Merkel cells drive pathological itch-scratch cycle in dry skin.