UC Berkeley

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the early development of itch, and the acute-to-chronic itch transition, remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch behaviors in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching behaviors in a mouse model of atopic dermatitis. Strikingly, neutrophils were required for several key hallmarks of chronic itch, including upregulation of inflammatory cytokines, skin hyperinnervation, enhanced expression of itch signaling molecules upregulation of activity-induced genes and markers of neuropathic itch in spinal cord and sensory ganglia. We also demonstrate that induction of CXCL10, a ligand for the CXCR3 receptor that promotes acute itch via direct activation of itch sensory neurons, is neutrophil-dependent. Indeed, we find that blockade of CXCR3 signaling attenuates atopic dermatitis itch. Our findings define a new role for neutrophils in atopic dermatitis, and establish the importance of CXCR3 signaling in bridging neutrophils and neurons in the transition from acute to chronic itch.