Luo J, et al. – The cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4)–mediated allergic and nonallergic chronic itch, were investigated in this study. The previously unrecognized mechanisms were unveiled. Through these mechanisms TRPV4–expressing epithelial and immune cells in the skin critically and dynamically mediated chronic itch and unraveled novel targets for therapeutics in the setting of chronic itch.