Transmembrane protein 45b in peripheral sensory neurons selectively mediates IL-31-dependent chemical itch

We previously identified transmembrane protein 45b (Tmem45b) as a pain-related molecule essential for mechanical pain hypersensitivity but not for thermal pain hypersensitivity. A subset of Tmem45b is expressed in TRPV1-positive primary afferents, which are specialized in transmitting thermal pain and specific types of itch. Here, we examined the involvement of Tmem45b in itch perception.

Behavioral experiments using Tmem45b knockout mice and wild-type mice were conducted to assess the role of Tmem45b in acute and chronic itch mediated by TRPV1-positive primary afferents. In addition, histochemical analyses were performed to identify Tmem45b-positive neurons in itch transmission.

Acute itch induced by interleukin (IL)-31 and compound 48/80 was significantly attenuated in Tmem45b knockout (KO) mice compared with wild-type (WT) mice, whereas acute itch induced by histamine, the protease-activated receptor-2 activating peptide SLIGRL-NH₂, and chloroquine remained unchanged. Similarly, chronic itch models induced by 2.4-dinitrofluorobenzene and imiquimod showed no significant differences between KO and WT mice. Histochemical analysis revealed that approximately 70% of dorsal root ganglion neurons that were double positive for Tmem45b mRNA and TRPV1 also expressed IL-31 receptor mRNA. Additionally, approximately 30% of dorsal root ganglion neurons that were double positive for Tmem45b mRNA and TRPV1 were also positive for natriuretic polypeptide B mRNA, a marker of pruriceptive afferents, suggesting their involvement in itch transmission.

These findings demonstrate that Tmem45b is selectively involved in IL-31-induced chemical itch and suggest that Tmem45b could serve as a novel modulator for IL-31-induced itch.