Origins of AD: Recent Advances

This paper reviews a study by Yadev et al. and further investigates the role of transient receptor potential ankyrin 1 (TRPA1) in the pathogenesis of atopic dermatitis (AD). The objective is to explore the molecular and cellular mechanisms underlying TRPA1-mediated itch, inflammation, and skin barrier dysfunction in AD, with an emphasis on its potential as a therapeutic target. By integrating experimental data from animal models, pharmacological interventions, and cellular assays, this study seeks to provide a deeper understanding of TRPA1’s involvement in AD and its broader implications for inflammatory skin diseases.

Summary

The study employed a comprehensive set of cellular, molecular, and animal model experiments to investigate the role of TRPA1 in AD.¹ Using murine models of AD, researchers observed significantly heightened expression of TRPA1 in both sensory neurons and keratinocytes within inflamed skin, correlating with increased itch behavior and robust inflammatory responses. Pharmacological inhibition of TRPA1 using selective antagonists markedly reduced pruritus and lowered levels of relevant proinflammatory cytokines, such as IL-4 and IL-13, as well as oxidative stress markers, highlighting the functional relevance of TRPA1 in AD pathogenesis. Calcium imaging of dorsal root ganglia neurons further confirmed that TRPA1 activation by reactive oxygen species (ROS) and environmental irritants led to pronounced intracellular calcium influx, which triggered the release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP).

In parallel, keratinocyte-focused assays revealed that TRPA1 activation disrupted tight junction integrity and impaired keratinocyte differentiation, contributing to compromised skin barrier function, a hallmark of AD. To explore the role of psychological stress in TRPA1-mediated AD exacerbation, the researchers exposed AD-prone mice to stress-inducing conditions and noted significant upregulation of TRPA1 expression alongside increased pruritic scratching and stress markers such as corticosterone. Importantly, pharmacological inhibition of TRPA1 mitigated these stress-induced exacerbations, further implicating the receptor in the link between stress and AD symptoms. Collectively, these findings integrate mechanistic insights from molecular assays, imaging studies, and animal models to highlight TRPA1 as a pivotal mediator of itch, inflammation, and barrier dysfunction in AD and underscore its potential as a therapeutic target.

Background and Study Results

TRPA1 is a versatile ion channel expressed in nociceptive neurons and keratinocytes, playing a critical role in neurogenic inflammation, oxidative stress, and sensory transduction. Its activation by exogenous irritants (eg, aldehydes, acrolein) and endogenous oxidative byproducts (eg, 4-hydroxynonenal, ROS) leads to the release of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP), amplifying inflammation and pain.^1,2 For instance, TRPA1 activation during experimental colitis models triggers the release of SP and CGRP, exacerbating intestinal inflammation.³ TRPA1 antagonists have shown potential in mitigating inflammatory and neuropathic pain, offering promising therapeutic avenues for diseases like migraines and chemotherapy-induced peripheral neuropathy.¹ Furthermore, TRPA1’s role in itch pathways—especially its upregulation in dorsal root ganglion neurons during inflammatory states—underscores its relevance in chronic dermatologic conditions like AD.⁴

In addition to its neuronal effects, TRPA1 contributes to skin barrier dysfunction and keratinocyte biology. While normally expressed at low levels in keratinocytes, TRPA1 expression is markedly upregulated by pro-inflammatory cytokines like TNF-α, mediated through NF-κB and MAP kinase pathways.⁵ Once activated, TRPA1 disrupts barrier homeostasis by altering keratinocyte proliferation and differentiation, as evidenced by changes in cyclin expression and heat shock protein levels upon exposure to TRPA1 agonists.⁶ This dysfunction contributes to the chronic inflammation and TEWL observed in conditions like AD. TRPA1’s sensitivity to temperature shifts and oxidative stress further implicates it in skin diseases exacerbated by environmental triggers.

The interplay between TRPA1 and oxidative stress deepens its involvement in inflammatory and systemic conditions. TRPA1’s activation by ROS perpetuates a feedback loop, where oxidative stress enhances TRPA1 signaling, further promoting inflammation.^2,3 This mechanism is evident in chemotherapy-induced peripheral neuropathy, where ROS-mediated TRPA1 activation drives hypersensitivity, reversible by TRPA1 inhibitors or antioxidants.^7,8 Similar processes occur in acute gout, where hydrogen peroxide-induced TRPA1 activation leads to pain and inflammation. Interestingly, in cancer cells, TRPA1 is co-opted to enhance oxidative stress tolerance and chemoresistance, with the NRF2 transcription factor directly regulating TRPA1 expression to support cell survival under oxidative stress.⁹ These findings suggest TRPA1’s dual role as a mediator of inflammation and a target for mitigating oxidative damage in both dermatologic and systemic diseases.

Psychological stress compounds TRPA1-mediated inflammation in AD, linking hormonal changes to sensory neuron activation. Elevated corticosterone levels during chronic stress influence nociceptors, altering the balance between cannabinoid (CB1) and TRPV1 receptor expression in sensory neurons, which modulates pain and stress responses.¹⁰ TRPA1, expressed in keratinocytes and sensory neurons, likely mediates these stress-induced changes, contributing to the heightened sensory perception and inflammation in AD.⁵ Stress reduction strategies or targeted interventions, such as corticoid receptor antagonists, could indirectly modulate TRPA1 activity, offering very solid evidence for taking a holistic approach to managing AD.

Finally, environmental exposures underscore TRPA1’s importance in dermatologic and systemic inflammation. Pollutants like cigarette smoke and vehicle exhaust contain aldehydes such as acrolein, potent TRPA1 agonists that trigger oxidative stress, neurogenic inflammation, and cardiopulmonary toxicity.^11,12 Animal models demonstrate that TRPA1 deficiency or inhibition confers resistance to acrolein-induced injuries, suggesting potential protective interventions for environmentally exacerbated diseases. Together, these findings highlight TRPA1’s broad implications in sensory, inflammatory, and systemic conditions, establishing it as a compelling therapeutic target.

Comments and Clinical Implications

The results of this study underscore TRPA1’s central role in AD, emphasizing its involvement in pruritus, inflammation, and skin barrier dysfunction. The upregulation of TRPA1 expression in both sensory neurons and keratinocytes within inflamed skin correlates with the exacerbation of symptoms, including heightened itch behavior and increased inflammatory responses. Pharmacological inhibition of TRPA1 significantly alleviated pruritus and reduced key inflammatory markers, such as IL-4 and IL-13, thereby highlighting the receptor’s potential as a therapeutic target for AD management. The study also reveals the interplay between TRPA1 and oxidative stress, which exacerbates inflammation, and how environmental irritants, such as pollutants, may amplify TRPA1 activity in AD. 

Furthermore, the role of psychological stress in increasing TRPA1 expression and aggravating AD symptoms offers new insights into the complex interactions between stress, sensory neuron activation, and skin inflammation. These findings suggest that therapeutic strategies aimed at modulating TRPA1 activity, either through selective antagonists or stress-reducing interventions, could provide a holistic approach to managing AD, addressing both the inflammatory and sensory components of the disease. 

Given the broad involvement of TRPA1 in sensory and systemic inflammation, its targeting holds promise for the development of novel treatments for AD and other inflammatory conditions exacerbated by environmental or psychological stress. 

References

1. Yadav M, Chaudhary PP, D’Souza BN, et al. Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1. PLoS One. 2023;18(3):e0282569. doi:10.1371/journal.pone.0282569

2. Nassini R, Materazzi S, Benemei S, Geppetti P. The TRPA1 channel in inflammatory and neuropathic pain and migraine. Rev Physiol Biochem Pharmacol. 2014;167:1-43. doi:10.1007/112_2014_18

3. Trevisani M, Siemens J, Materazzi S, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007;104(33):13519-13524. doi:10.1073/pnas.0705923104

4. Engel M, Leffler A, Niedermirtl F, et al. TRPA1 and substance P mediate colitis in mice. Gastroenterology. 2011;141(4):1346-1358. doi:10.1053/j.gastro.2011.07.002

5. Wang X, Cui L, Liu Z, et al. Effects of TRPA1 activation and inhibition on TRPA1 and CGRP expression in dorsal root ganglion neurons. Neural Regen Res. 2019;14(1):140-148. doi:10.4103/1673-5374.243719

6. Luostarinen S, Hämäläinen M, Moilanen E. Transient receptor potential ankyrin 1 (TRPA1)—an inflammation-induced factor in human HaCaT keratinocytes. Int J Mol Sci. 2021;22(7):3322. doi:10.3390/ijms22073322

7. Atoyan R, Shander D, Botchkareva NV. Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin. J Invest Dermatol. 2009;129(9):2312-2315. doi:10.1038/jid.2009.58

8. Trevisan G, Materazzi S, Fusi C, et al. Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res. 2013;73(10):3120-3131. doi:10.1158/0008-5472.CAN-12-4370

9. Trevisan G, Hoffmeister C, Rossato M, et al. TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger hyperalgesia and inflammation in a model of acute gout. Free Radic Biol Med. 2014;72:200-209. doi:10.1016/j.freeradbiomed.2014.04.021

10. Takahashi N, Chen HY, Harris IS, et al. Cancer cells co-opt the neuronal redox-sensing channel TRPA1 to promote oxidative-stress tolerance. Cancer Cell. 2018;33(6):985-1003. doi:10.1016/j.ccell.2018.05.001

11. Hong S, Zheng G, Wu X, et al. Corticosterone mediates reciprocal changes in CB1 and TRPV1 receptors in primary sensory neurons in the chronically stressed rat. Gastroenterology. 2011;140(2):627-637. doi:10.1053/j.gastro.2010.11.003

12. Simon SA, Liedtke W. How irritating: the role of TRPA1 in sensing cigarette smoke and aerogenic oxidants in the airways. J Clin Invest. 2008;118(7):2383-2386. doi:10.1172/JCI36111

13. Conklin DJ. Acute cardiopulmonary toxicity of inhaled aldehydes: role of TRPA1. Ann N Y Acad Sci. 2016;1374(1):59-67. doi:10.1111/nyas.13055

Janmesh D. Patel reports no conflicts of interest. Dr. Lio reports being on the speaker’s bureau for AbbVie, Arcutis, Eli Lilly, Galderma, Hyphens Pharma, Incyte, La Roche-Posay/L’Oreal, Pfizer, Pierre-Fabre Dermatologie, Regeneron/Sanofi Genzyme, Verrica; reports consulting/advisory boards for Alphyn Biologics (stock options), AbbVie, Almirall, Amyris, Arcutis, ASLAN, Bristol-Myers Squibb, Burt’s Bees, Castle Biosciences, Codex Labs (stock options), Concerto Biosci (stock options), Dermavant, Eli Lilly, Galderma, Janssen, LEO Pharma, Lipidor, L’Oreal, Merck, Micreos, MyOR Diagnostics, Regeneron/Sanofi Genzyme, Sibel Health, Skinfix, Suneco Technologies (stock options), Theraplex, UCB, Unilever, Verdant Scientific (stock options), Verrica, Yobee Care (stock options). In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member emeritus of the National Eczema Association.