Figure 1. Keratinocyte-Derived TSLP Directly Activates Primary Sensory Afferents to Evoke Itch.

(A) Endogenous and exogenous proteases activate PAR2 signaling in keratinocytes. PAR2 activation triggers Ca²⁺ release from and depletion within the ER, which subsequently stimulates STIM1-mediated opening of ORAI1 channels on the plasma membrane. Ca²⁺ influx into keratinocytes triggers calcineurin-dependent dephosphorylation and nuclear translocation of NFAT. NFAT activation induces transcription of TSLP. Secreted TSLP acts directly on immune cells and nerves. (B) Keratinocyte-derived TSLP binds to the heterodimeric TSLP receptor on peripheral afferent C-fibers, activating the PLC signaling pathway and resulting in the opening of TRPA1 ion channels. TRPA1 activation stimulates membrane depolarization and initiates neural signaling cascades that result in the sensation of itch.