Molecular Signature of Pruriceptive MrgprA3⁺ Neurons

Itch, initiated by the activation of sensory neurons, is associated frequently with dermatological diseases. MrgprA3⁺ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulation of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here, we performed RNA sequencing of genetically labeled MrgprA3⁺ neurons under both naïve and allergic contact dermatitis conditions. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3⁺ neurons, suggesting that MrgprA3⁺ neurons are a direct neuronal target for histamine and Mrgpr agonists. In addition, PTPN6 and PCDH12 were identified as highly selective markers of MrgprA3⁺ neurons. We also discovered that MrgprA3⁺ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potential targets for combating itch.