This web page was produced as an assignment for an undergraduate course at Davidson College.
Transgenic mice and house dust mites uncover key insights regarding the roles of PAR2 overexpression and environmental exposure to allergens in atopic dermatitis.
Atopic Dermatitis (AD) is a major inflammatory skin condition that is characterized by itching and irritation of the skin (Leung et al. 2004). This condition affects millions of people worldwide, including 10-20% of children and 1-3% of adults (Leung et al. 2004). Dermatitis is a complex illness due to the fact that it does not have one distinct form or cause. Rather, it refers to a broad spectrum of skin conditions that manifest themselves in a variety of forms (Garibyan et al. 2013). The phenotype that characterizes dermatitis is caused by a combination of factors, including susceptibility genes, environmental allergens, and defective skin barrier functioning to name a few (Leung et al. 2004).
Incessant itching is the primary criteria for clinical diagnosis of atopic dermatitis (Braz et al. 2021). One of the major contributors to the pruritis, or itching, seen in dermatitis is environmental allergens (Moses, 2003). The common house dust mite (HDM) is a major environmental allergen that has been correlated with AD and asthma in humans (Krämer et al. 2005). HDM exposure triggers a large and multifaceted allergic immune response.
HDM proteases, enzymes which breakdown proteins, activate protease-activated receptors (PARs). One of these receptors, PAR2, is activated by HDM proteins that are released in inflamed skin (Braz et al. 2021). PAR2-expressing sensory neurons are responsible for the physical symptoms of dermatitis. These sensory neurons transmit pain through nociceptors and itch through pruritoceptors (Braz et al. 2021).
PAR2 is overexpressed in the skin of AD patients who experience both pain and itch. However, even though PAR2-activating proteases are abundant in inflamed atopic skin, little is known about the PAR-mediated mechanisms that contribute to allergic itch. To address this question, Braz et al. examined the molecular and behavioral consequences of HDM on PAR2- overexpressed transgenic mice (Grhl3PAR2/+). Transgenic mice are genetically modified mice. In this experiment, the researchers genetically modified mice to overexpress PAR2 in order to examine its contributions to the behavioral and molecular effects of dermatitis.
To examine the effects of environmental allergens on dermatitis in mice, the researchers treated one cheek of wild-type and Grhl3PAR2/+ mice with a chemical solution that disrupts skin barriers. Next, they treated an experimental group of wild-type and Grhl3PAR2/+ mice with HDM, while the control group was given vaseline. 40% of HDM-treated transgenic mice exhibited severe spontaneous scratching and skin changes consistent with the dermatitis-phenotype (Braz et al. 2021). Surprisingly, however, another 40% of HDM-treated Grhl3PAR2/+ mice did not experience any notable behavioral or physiological symptoms of dermatitis. The researchers referred to these two groups of mice as responder and non-responder mice, respectively.
To identify how the patterns of gene expression differ between responder and non-responder mice, the researchers performed RNA-seq on the terminal ganglia (TG) that supply the cheek with nerves. RNA-seq was conducted on both the treated and untreated cheeks of the mice. The gene expression patterns of the HDM-treated responder group differed markedly from all of the other groups. In nonresponder mice, the researchers only recorded 15 up-regulated and 6 down-regulated genes in the TG treated with HDM. Conversely, there were over 100 up-regulated genes in the responder mice treated with HDM (Braz et al. 2021).
To evaluate these findings in another model of dermatitis, the researchers examined gene expression patterns in cervical DRG ganglia. These transcriptional changes were very similar in magnitude to those exhibited by the HDM-treated PAR2 responders. This led the researchers to suggest that a common sensory neuron gene expression program is induced in multiple dermatitis models. More specifically, PAR2 overexpression in the skin primes the neurosensory circuits. Through these neurosensory circuits (ganglia), environmental allergen exposure modulates the transmission of signals for pain and itching.
It is intriguing to think that there may be a genetic priming program in sensory neurons that is activated by environmental allergens. The knowledge that environmental allergens may play a significant role in the exacerbation of chronic atopic dermatitis has important implications on the diagnosis and treatment of the condition. This study uncovers an interesting intersection between immunology and dermatology and raises the possibility of combining treatment in these fields to help reduce the severity of AD. However, there are also some notable limitations to this study that must be addressed. This experiment is only looking at one specific environmental allergen and one gene linked to AD susceptibility. There are countless susceptibility genes and environmental allergens that may contribute to AD. Therefore, until more research is done, we can’t know whether similar sensory neuron gene expression programs are present in more dermatitis models.
This experiment provides an important gateway into obtaining a greater understanding of the underlying molecular mechanisms influencing dermatitis. In science, knowledge is power, and the more we learn about the underlying causes of atopic dermatitis, the better chance we have of stumbling upon potential treatments and therapies that could improve the lives of people suffering from skin conditions.
Kade McCulloch is a Sophomore Biology Major and Public Health Minor at Davidson College. Contact him at kamcculloch@davidson.edu!
––––––––––––––––––––––
Resources
Braz, J.M., Dembo, T., Charruyer, A., et al. Genetic priming of sensory neurons in mice that overexpress PAR2 enhances allergen responsiveness, PNAS, 2021; 118 (8) e2021386118
Krämer, U., Weidinger, S., Darsow, U., et al. Seasonality in symptom severity influenced by temperature or grass pollen: results of a panel study in children with eczema, Journal of Investigative Dermatology, 2005; Vol. 1 Issue 3; 514-523
Leung, D.Y.M., Boguniewicz, M., Howell, M.D, et al. New insights into atopic dermatitis, The Journal of Clinical Investigation, 2004.
Moses, Scott. Pruritis, American Family Physician, 2003; 15;68(6):1135-1142.
© Copyright 2020 Department of Biology, Davidson College, Davidson, NC 28036
