Tacrolimus suppresses itch-related response in diet-induced atopic dermatitis model mice by reducing chloroquine-sensitive sensory neurons

Introduction: Itch (or pruritus) is a common symptom of atopic dermatitis (AD), which significantly decreases the patient’s quality of life. Tacrolimus ointment reduces pruritus in AD; however, the underlying mechanism is not fully understood. Methods: In the present study, we used a diet-induced AD mouse model to examine the antipruritic mechanism of tacrolimus. After induction of AD symptoms, the tacrolimus-containing ointment was applied once daily for 7 days. Responsiveness of isolated dorsal root ganglion (DRG) cells to various stimuli was examined by monitoring intracellular Ca2+ levels. Results: Repeated application of tacrolimus ointment attenuated spontaneous itch-related responses, even when skin barrier dysfunction, skin inflammation, and epidermal nerve sprouting were not ameliorated. Tacrolimus-treated mice also exhibited reduced scratching behavior induced by several pruritogens, such as histamine, SLIGRL-NH2, and chloroquine (CQ), although capsaicin-induced pain behavior was not affected. DRG cells from tacrolimus-treated mice showed significantly lower Ca2+ responses to CQ. Furthermore, a reduction in CQ-sensitive DRG neurons was observed after in vitro treatment with either tacrolimus or rapamycin. Discussion: CQ-sensitive (MrgprA3-expressing) DRG neurons are implicated as itch-specific sensory neurons. Therefore, topically applied tacrolimus may act directly on itch-signaling neurons, consequently suppressing various itch responses in AD mice.