2021.02.26 Journal Club

Genetic priming of sensory neurons in mice that overexpress PAR2 enhances allergen responsiveness

Joao M. Braza,1, Todd Demboa,1, Alexandra Charruyerb, Ruby Ghadiallyb,c, Marlys S. Fassettc,d, and Allan I. Basbauma,2

aDepartment of Anatomy, University of California, San Francisco, CA 94158; bDivision of Dermatology, San Francisco Veteran’s Administration Medical Center, San Francisco, CA 94121; cDepartment of Dermatology, University of California, San Francisco, CA 94158; and dDepartment of Microbiology and Immunology, University of California, San Francisco, CA 94158

Contributed by Allan I. Basbaum, January 13, 2021 (sent for review October 14, 2020; reviewed by Diana M. Bautista and Earl Carstens)

Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neu- rons that transmit pruritic signals are well-cataloged, little is known about the neuronal alterations that occur as a result of skin disruption in AD. To address this question, we examined the mo- lecular and behavioral consequences of challenging Grhl3PAR2/+ mice, which overexpress PAR2 in suprabasal keratinocytes, with serial topical application of the environmental allergen house dust mite (HDM). We monitored behavior and used RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in tri- geminal ganglia (TG), before and after HDM. We found that nei- ther Grhl3PAR2/+ nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in Grhl3PAR2/+ mice. Despite the absence of scratching in untreated Grhl3PAR2/+ mice, several TG genes in these mice were up-regulated compared to WT. HDM treat- ment of the Grhl3PAR2/+ mice enhanced up-regulation of this set of genes and induced additional genes, many within the subset of TG neurons that express TRPV1. The same set of genes was up- regulated in HDM-treated Grhl3PAR2/+ mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcrip- tional changes in IL31Tg mice, demonstrating that a common ge- netic program is induced in two AD models. Taken together, we conclude that transcriptional changes that occur in primary sensory neurons in dermatitis-susceptible animals underlie a genetic priming that not only sensitizes the animal to chronic allergens but also contributes to pruritus in atopic skin disease.

itch | dermatitis | trigeminal neurons | PAR2 | RNA sequencing