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Pruritus is a common symptom of inflammatory skin conditions, including atopic dermatitis (AD). Although primary sensory neurons 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 molecular and behavioral consequences of challenging Grhl3 PAR2/+ 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 trigeminal ganglia (TG), before and after HDM. We found that neither Grhl3 PAR2/+ nor wild-type (WT) mice exhibited spontaneous scratching, and pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated scratching in Grhl3 PAR2/+ mice. Despite the absence of scratching in untreated Grhl3 PAR2/+ mice, several TG genes in thesemice were up-regulated compared to WT. HDM treatment of the Grhl3 PAR2/+ 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 upregulated in HDM-treated Grhl3 PAR2/+ mice that did not scratch, but at lesser magnitude. Finally, we recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a common genetic 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.

Chronic pain and itch pose ever present, steadily growing burdens to human health. Still, we have limited understanding of the mechanisms that underlie their development and persistence. Furthermore, treatments for these conditions tend to be palliative, rather than curative, leading to mixed patient outcomes. With this in mind, we used next generation sequencing to assemble a transcriptional profile of the molecular changes in skin and sensory neurons that associate with a unique, stochastic mouse model of atopic dermatitis. This model combines the genetic sensitization of a PAR2 overexpression animal with environmental challenge by house dust mite allergens. To our knowledge, this is the first profiling effort that broadened its focus beyond the skin to look at the important, itch-facilitating contribution of sensory neurons. An interesting feature of this PAR2 model is that, by virtue of its stochasticity, it may allow for the independent identification of both protective and deleterious changes. These datasets will serve as useful resources for clinicians and researchers interested in the pathogenesis and prevention of atopic dermatitis. Among the many genetic changes detected in our analysis was brain-derived neurotrophic factor (BDNF), which is expressed by sensory neurons and has been repeatedly implicated in different pain and itch conditions. Thus, in a parallel series of studies, we investigated the neuronal expression pattern and behavioral contributions of primary afferent-derived BDNF. Contrary to previous reports, we found that BDNF expression within dorsal root ganglia predominates in large-diameter, myelinated neurons. Furthermore, we found little evidence that BDNF contributes significantly to acute or chronic pain, with one notable exception observed in the formalin test of inflammatory pain. The selective deletion of BDNF from primary sensory neurons markedly reduced nocifensive behaviors during the second phase of the formalin test, which is thought to model tissue injury-induced post-operative pain. Surprisingly, this difference was sexually dimorphic, and only occurred in male mice. However, based on its expression pattern within sensory ganglia and its minimal apparent contribution to pain or itch, we suggest that, in the future, primary afferent-derived BDNF should be studied in the context of low-threshold mechanotransduction.

The tumor microenvironment (TME) plays a central role in cancer progression, treatment response, and patient outcomes, yet large-scale, consistent, and quantitative TME characterization from routine hematoxylin and eosin (H&E)-stained histopathology remains scarce. We introduce OpenTME, an open-access dataset of pre-computed TME profiles derived from 3,634 H&E-stained whole-slide images across five cancer types (bladder, breast, colorectal, liver, and lung cancer) from The Cancer Genome Atlas (TCGA). All outputs were generated using Atlas H&E-TME, an AI-powered application built on the Atlas family of pathology foundation models, which performs tissue quality control, tissue segmentation, cell detection and classification, and spatial neighborhood analysis, yielding over 4,500 quantitative readouts per slide at cell-level resolution. OpenTME is available for non-commercial academic research on Hugging Face. We will continue to expand OpenTME over time and anticipate it will serve as a resource for biomarker discovery, spatial biology research, and the development of computational methods for TME analysis.