Skin inflammation and itch response are independently regulated by distinct nociceptor subsets.

Common dermatological disorders are characterized by inflammation and severe itching, which represent a significant clinical challenge. The mechanisms by which nociceptive sensory neurons (nociceptors) integrate peripheral signals to modulate inflammation and itch remain unclear. Here, we showed that two subsets of nociceptors had distinct and nonredundant biological functions in a model of allergic contact dermatitis (ACD). Retrograde axonal tracing of skin-projecting neurons combined with single-cell profiling identified a subset of MrgprD+ nonpeptidergic neurons that adopted a transitory regenerative program in response to skin inflammation. Selective ablation of reprogrammed MrgprD+ nonpeptidergic neurons during ACD-like inflammation abolished itch-evoked behavior but did not affect skin inflammation. Conversely, selective depletion of Trpv1+ peptidergic neurons exacerbated inflammation through increased neutrophilic infiltration without impacting itch-evoked behavior. This study reveals the presence of two distinct and adaptive neuronal circuits that independently regulate allergic inflammation and itch in the skin.