Fig 2: TM5275 attenuates MC903-mediated itch, epidermal hyperplasia, and reduces the expression of Serpin E1, and OSM in the skin of MC903-mice. (A) Immunocyte cell number in MC903-mice treated with or without TM5275. Representative HE staining (B) and ear skin epidermal thickness analysis (C) in MC903-mice with or without TM5275 treatment. (D) TM5275 attenuated itch-like behavior in MC903-mice. (A) RNA-seq showing upregulation of transcripts of PLAUR, Serpin E1, OSMR, and OSM in ear skin from MC903-mice. (F) Representative images showing T5275 reduced expression of Serpin E1 and OSM in ear skin from MC903-mice. Data in A–C are means ± SEMs; All data in D,E are from n = 6–8 mice/group. For A, C and F, data are from (n = 4 mice/group). For (E), ***FDR < 0.001. For A and C, N.S., p > 0.05, *p < 0.05, and ***p < .001, student t test; for (F), ***p < .001, one-way ANOVA. (F) Schematic showing signaling pathways for PLAUR-TLR2 in chronic itch. Serpin E1 receptor PLAUR and TLR2 are upregulated in AD skin from patients and mouse models. Serpin E1 activated PLAUR in TLR+-neurons, leading to transcriptional upregulation of TLR2 and its co-signaling proteins. TLR2 in turn promotes gene transcription of critical itch mediators including BNP and OSM, as well as AD-associated PAR2. OSM induces acute itch-like behaviors in mice and promotes inflammatory mediator release from human keratinocytes. Serpin E1 facilitates transcription/expression levels of Serpin E1 and OSM. This study uncovered that PLAUR is a new pruritogenic receptor in promoting AD itch. We propose targeting PLAUR represents a novel target for the therapeutic development of treating AD itch and skin inflammation