Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis

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. Neutrophils were also required for several key hallmarks of chronic itch, including upregulation of inflammatory cytokines, skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of activity-induced genes and markers of neuropathic itch. Finally, we demonstrate that induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, is neutrophil-dependent and that CXCR3 antagonism attenuates chronic itch.