Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2025;15(4):5329 1 Skin-Immune-Neuro-Gastro-Endocrine (SINGE) System: Lighting the Fire on Atopic Dermatitis Research Meshi Paz1, Peter Lio2,3 1 Tulane University School of Medicine, New Orleans, USA 2 Feinberg School of Medicine, Northwestern University, Chicago, USA 3 Medical Dermatology Associates of Chicago, Chicago, USA Key words: Atopic dermatitis, Neuroimmunology, Gut-skin axis, Itch-scratch cycle, Neuroendocrine microbiome Citation: Paz M, Lio P. Skin-Immune-Neuro-Gastro-Endocrine (SINGE) System: Lighting the Fire on Atopic Dermatitis Research. Dermatol Pract Concept. 2025;15(4):5329. DOI: https://doi.org/10.5826/dpc.1504a5329 Accepted: April 1, 2025; Published: October 2025 Copyright: ©2025 Paz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: Dr. Peter Lio reports research grants/funding from AbbVie, AOBiome, and Regeneron/Sanofi, Genzyme, is on the speaker’s bureau for AbbVie, Eli Lilly, Galderma, Hyphens, Incyte, LEO Pharma, L'Oreal, MyOR Diagnostics, ParentMD, Pfizer, and Regeneron/Sanofi Genzyme, and reports consulting/advisory boards for AbbVie, Almirall, Amyris, AOBiome, Arbonne, ASLAN Pharmaceuticals, Burt’s Bees, Castle Biosciences, Codex Labs, Concerto Biosciences (stock options), Dermavant, Eli Lilly, Exeltis, Galderma, IntraDerm, Johnson & Johnson, LEO Pharma, L’Oreal, Menlo Therapeutics, Micreos, Pfizer, Pierre-Fabre, Regeneron/Sanofi Genzyme, Theraplex, and Unilever. 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 of the National Eczema Association. Meshi Paz reports no conflicts of interest. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Dr. Peter Lio, MD, Medical Dermatology Associates of Chicago, 363 W Erie Street #360, Chicago, IL 60654. ORCID: 0000-0001-7600-0152. Email: peterlio@gmail.com Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by pru- ritic, dry, eczematous lesions. Traditionally regarded primarily as a cutaneous disorder influenced by genetic and environmental factors, AD is increasingly recognized as a multisystem condition involving immune, microbial, and neuroendocrine interactions. Objectives: This review proposes the Skin-Immune-Neuro-Gastro-Endocrine (SINGE) network as a comprehensive framework to explore the interconnected pathophysiology of AD. The aim is to highlight how changes across various systems contribute to disease development, presentation, and treatment. Methods: A comprehensive review of current literature was performed, examining the roles of skin barrier dysfunction, immune signaling, neuroendocrine pathways, and gut microbial dysbiosis. These domains were integrated into a unified model that describes bidirectional interactions and their clin- ical implications. Results: The SINGE model reveals that epidermal barrier disruption activates a cascade of immune responses. Microbial dysbiosis, in concert with the gut-skin axis, further exacerbates AD symptoms, highlighting how alterations in one organ affect the other. Neuroinflammation further contributes ABSTRACT 2 Review | Dermatol Pract Concept. 2025;15(4):5329 Introduction Atopic dermatitis (AD) is a chronic inflammatory skin dis- ease that presents as pruritic, dry, eczematous skin that is prevalent among 10%–30% of children and 2%-10% of adults [1,2]1. The etiology of AD is complex, involving a combination of environmental triggers and a genetic pre- disposition [2]. The most notable genetic mutation has been seen involving filaggrin (FLG), which encodes an epidermal protein that maintains skin integrity and moisture [2]. The characteristic skin barrier dysfunction and immune dysreg- ulation seen in AD often accompanies other IgE-associated diseases like asthma and allergic rhinitis, together known as the atopic triad [1,3,4]. Recognizing this heterogeneity is crucial to advancing precision medicine approaches in AD. The psychosocial comorbidities associated with this disease and the increased risk of multisystem involvement empha- sizes the extent and burden of AD. [5]. The multisystem impact of AD is intricately linked to both the neuro-immuno-cutaneous-endocrine (NICE) net- work and the gut-skin axis, offering insight into the com- plex pathophysiology of the disease. Neuropeptides like calcitonin gene-related peptide (CGRP), substance P, and vasoactive intestinal peptide (VIP) promote inflammation via cutaneous nerves. Neuroendocrine mediators, including glucocorticoids, are produced in response to stress and ac- tivate the hypothalamic-pituitary-adrenal (HPA) axis and subsequent hormonal cascades [6]. Furthermore, overactiva- tion of the Th2 immune response increases levels of IL-4 and IL-13 during disease flares (Figure 1) [7]. Additionally, gut dysbiosis, increased intestinal perme- ability, and changes in microbial metabolic byproducts ex- acerbate systemic inflammation, intensifying the hallmark itch-scratch cycle through neural and immune systems [8]. Collectively, these interconnected systems contribute to the multifaceted nature of AD pathology [9]. In addition to its systemic impact, AD is a highly het- erogeneous disease, exhibiting variability in clinical pre- sentation, pathophysiology, and treatment response. While inflammation in AD is primarily driven by the Th2 mech- anism, recent studies have found Th1, Th17, and Th22 pathways implicated in some populations as well [10,11]. Moreover, the classification of intrinsic and extrinsic AD phenotypes further highlights the disease variability, with the two phenotypes differing in their IgE levels, epidermal bar- rier dysfunction, and immune activation pathophysiology [11,12]. Appreciating the heterogeneity of AD is essential to advancing individualized and comprehensive treatment approaches. Objective This paper proposes the Skin-Immune-Neuro-Gastro- Endocrine (SINGE) network as a framework to investigate the multisystem contributions of AD. By encapsulating the intricate connections between the systems, this study aimed to explore biomarkers and pathways involved in the disease pathogenesis in hopes of laying the foundation for future targeted treatments and ultimately enhancing patient care (Figure 2). SINGE versus NICE systems While the two systems have great overlap, they propose dis- tinct approaches to understanding cutaneous disorders. The NICE network primarily highlights the bidirectional cross- talk between the skin, immune system, nervous system, and endocrine pathways. It emphasizes how stress-induced neu- roendocrine signaling exacerbates immune-mediated cutane- ous inflammation. Although the NICE system takes stress responses into account, it does not explicitly integrate the crucial role of the gastrointestinal (GI) system, which has emerged as a key contributor to systemic immune and in- flammatory pathways. The SINGE network builds upon the NICE framework by integrating the GI contributions to systemic inflamma- tion and immune responses in AD. This addition accounts for the roles of the gut microbiome and the epithelial barrier dysfunction, both skin and intestinal, that contribute neuro- endocrine signaling and immune responses [27,28]. As such, the SINGE system lays the foundation for a more compre- hensive framework for understanding AD. to AD symptoms by perpetuating the itch-scratch cycle. Neuroendocrine factors amplify the inflam- matory dysregulation, particularly through endocrine involvement involving cortisol signaling in the hypothalamic-pituitary-adrenal (HPA) axis and the paradoxical inflammatory effects on the skin bar- rier. Together, these intertwined pathways perpetuate the chronic inflammation and skin barrier dys- function in AD. Conclusion: By examining these elements as an intricate, intertwined system, the SINGE network reframes AD as a multisystem condition. This apprach not only shifts the understanding of the disease, but also serves as a foundation for exploration of targeted therapies. Review | Dermatol Pract Concept. 2025;15(4):5329 3 Immune Involvement in AD The epithelia serve as the first line of defense in the immune system through their physical barrier function. Keratino- cytes in the epidermis play a key role in maintaining bar- rier integrity through tight junctions and FLG production [10]. Additionally, these cells engage the immune system by generating cytokines, signaling through major histocompat- ibility complex (MHC) class I and II proteins and produc- ing antimicrobial peptides like cathelicidins and defensins. Toll-like receptors (TLRs) on keratinocytes interact with pathogen-associated molecular patterns (PAMPs) to detect harmful microbes, facilitating immune surveillance and maintaining a healthy skin microbiome [10,11]. Other cells, such as Langerhans cells and dendritic cells, recognize and present antigens to lymphocytes. T and B lymphocytes, mac- rophages, mast cells, and eosinophils also function in the skin to amplify the immune response [11,12]. Collectively known as the skin-associated lymphoid tissue (SALT), this network of cells bridges the innate and adaptive immune re- sponses [11]. In AD, skin barrier dysfunction lays the foundation for disease progression. The epithelial barrier hypothesis sug- gests that initial disturbances, whether from FLG dysfunc- tion or external triggers, allow allergens and pathogens to penetrate the skin surface, leading to chronic inflammation due to an overactive Th2 pathway seen in AD [13,14]. This Figure 1. The NICE System and Gut-Skin Axis. The NICE system (left) illustrates the multisystem crosstalk affecting skin health. The gut-skin axis (right) depicts the bidirectional communication between the two organs, suggesting that the dysfunction of one organ can influence the other. Expanding on these concepts, the SINGE network synthe- sizes both frameworks to provide a more comprehensive understanding of AD pathogenesis. Figure 2. The Skin-Immune-Neuro-Gastro-Endocrine (SINGE) Network in atopic der- matitis (AD). The SINGE network illustrates the multisystem interactions involved in AD. Each system, interconnected by bidirectional communication, contributes to the cycle of disease progression in response to internal and external triggers. 4 Review | Dermatol Pract Concept. 2025;15(4):5329 Neuro/Nervous Involvement in AD Neuroinflammation further facilitates AD pathogenesis by exacerbating both disease severity and symptom progression. As previously noted, immune mediators stimulate cutaneous sensory nerves, intensifying the itch-scratch cycle [8,22,23]. Individuals with AD have alterations of these nerves, includ- ing differences in density, abnormal morphology, and elec- trophysiologic properties, which may strengthen signaling to the brain and prompt a scratching response [8,24,25]. Neuropeptides play a crucial role in neurogenic inflamma- tion. In response to a trigger, these vasoactive peptides attract inflammatory mediators like mast cells [26]. Neuropeptides also stimulate keratinocyte proliferation, leading to and epidermal thickening, which are key aspects of eczematous lesions [23]. Substance P (SP), markedly overexpressed in those with AD, drives itch perception by provoking mast cell degranu- lation [23,26]. Interestingly, SP is also produced by kerati- nocytes, suggesting its utility as a potential target for future therapies [23]. By activating immune responses and main- taining bidirectional interactions with the skin, SP serves as a critical connector between various systems. Another significant pro-inflammatory neuropeptide in- volved in AD pathogenesis is calcitonin gene-related peptide (CGRP). Elevated in response to AD exacerbations, CGRP affects both central pruritus and peripheral neuroinflam- mation [8]. It activates immune responses by activating dendritic cells and Th2 cells as well as inducing epidermal changes through keratinocyte proliferation [8,17]. Further, pathogens like S. aureus directly stimulate local CGRP re- lease, thus impairing bacterial clearance by modulating the immune response [17]. inflammatory response results in increased activity of cyto- kines like IL-4, IL-5, and IL-13, which further impair the skin barrier by inducing keratinocyte apoptosis and disrupting essential barrier proteins [1,12,14]. The resulting transepi- dermal water loss and susceptibility to pathogen infiltration exacerbates AD symptoms like dry skin and pruritus [14,15] (Figure 3). While the acute phase of AD is mediated by Th2 overac- tivity, the chronic state of this disease demonstrates a shift to more Th1/Th22 signaling [1,15]. Th1 engagement leads to increased circulating proinflammatory cytokines like IL- 1, while Th22 excitement stimulates skin remodeling and thickening. Together, this chronic immune activation causes epidermal thickening and hyperplasia [1,16]. Central to the manifestations of chronic AD is the itch-scratch cycle, where immune-mediated inflammation induces pruritus, leading to scratching that worsens skin barrier integrity and exacerbates AD symptoms [17]. The immune response communicates with cutaneous nerves through cytokines like IL-4, IL-13, and IL-31 [18,19]. IL- 31, in particular, is known as the “itch cytokine” for its pivotal role in enhancing the sensitivity of these nerves, intensifying chronic itch sensation through neuroimmune pathways [8,19] (Figure 4). The disrupted skin barrier in AD also predisposes to mi- crobial colonization, notably Staphylococcus aureus, which worsens the disease severity and leads to a microbial dys- biosis. This imbalance heightens the Th2 immune response and increases the risk of infection, underscoring the intricate relationship between microbial colonization and immune dysregulation in AD [20,21]. Figure 3. Pathophysiology of atopic dermatitis (AD). In AD, the skin barrier dysfunction (1) allows allergens, irritants, and pathogens (2) to penetrate into the skin (3), activating an exaggerated Th2 immune response (4). The subsequent cytokine release, including IL-4, IL-5, IL-13, and IL-31 (5), further weakens the skin barrier integrity, leading to water loss and worsening symptoms (6). Review | Dermatol Pract Concept. 2025;15(4):5329 5 [30]. Gut dysbiosis is also linked to altered neuroendocrine sig- naling by modulating serotonin and GABA levels, which both further regulate AD symptoms. The gut-skin connection offers potential as a therapeutic target by leveraging the microbiotic and metabolic contributions. Diet modifications, probiotics, and postbiotics are being explored for their ability to reduce AD burden on affected individuals [28]. Given the extensive contributions by the gut-skin axis, it is imperative to incorporate the GI system into understand- ing dermatological diseases, especially systemic conditions like AD. Thus, the addition of this organ system into the SINGE framework strengthens knowledge of the disease. Endocrine Involvement in AD The endocrine system contributes to the pathophysiology of AD, primarily through the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, this axis activates a cascade of hormonal responses involving corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), leading to increased cortisol production. While it is an es- sential anti-inflammatory hormone, in AD, cortisol para- doxically contributes to the characteristic inflammation by impairing keratinocyte proliferation and barrier integrity due to dysfunctional signaling within the epidermis [30,31]. Gastrointestinal Involvement in AD The gut-skin axis further highlights the multisystem reach of AD, with gut microbiota serving a crucial role in the cross- talk between these organs. Similar to the skin microbiome, the gastrointestinal tract houses a multitude of microorgan- isms and thus contributes to the development of the immune system [27]. When disrupted, the gut microbiome demon- strates a reduced microbial diversity, a decrease in benefi- cial bacteria like Bifidobacterium and Lactobacillus, and an increase in harmful species like Clostridium difficile and Escherichia coli. These changes contribute to increased gut permeability, allowing inflammatory agents to enter the sys- temic circulation and exacerbate skin inflammation [27,28]. Microbial metabolites play a central role in the gut-skin axis, influencing immune responses, neuroendocrine-induced inflammation, and skin barrier integrity [27]. Short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate alter the circulating levels of neuroendocrine and immuno- logical mediators [28,29]. For example, butyrate promotes T cell function and enhances epithelial barrier integrity, al- together mitigating inflammation [27]. Microbial dysbiosis, on the other hand, can activate immune responses through dysbiosis-associated metabolites including lipopolysaccharides, which trigger pro-inflammatory cytokines and exacerbate AD Figure 4. The itch-scratch cycle. The itch-scratch cycle perpetuates skin damage and inflammation, driving the pruritus seen in atopic dermatitis. The itch sensation triggers a scratching response, which worsens inflammation and epidermal barrier damage, fur- ther fueling the cycle. 6 Review | Dermatol Pract Concept. 2025;15(4):5329 targeting neuropeptides, such as SP and CGRP antagonists, are being explored as possible approaches to inhibit itch and neurogenic inflammation [40-42]. Given the role of the HPA axis in AD exacerbations, treatment aimed at mod- ulating the dysregulated endogenous cortisol production rather than simply supplementing with exogenous corti- costeroids may help address stress-induced flares [31,32]. Along a similar logic, psychosocial therapies could also mitigate the disease burden alongside medical treatment [33,35]. Considering the heterogeneity of AD, with diverse clinical presentations and immune profiles, future research should explore targeted, individualized therapies that ac- count for this variability by leveraging the multiple systems of the SINGE network to better develop integrative thera- pies. This interconnected, holistic approach to studying AD paves the way for innovation that could improve patient outcomes and quality of life. References 1. Afshari M, Kolackova M, Rosecka M, Čelakovská J, Krejsek J. Unraveling the skin; a comprehensive review of atopic dermati- tis, current understanding, and approaches. Frontiers in Immu- nology. 2024;15. DOI:10.3389/fimmu.2024.1361005. PMID: 38500882 2. Kolb L, Ferrer-Bruker SJ. Atopic Dermatitis. In: StatPearls. Stat- Pearls Publishing; 2024. PMID: 28846349 3. Magnifico I, Petronio Petronio G, Venditti N, et al. Atopic Der- matitis as a Multifactorial Skin Disorder. Can the Analysis of Pathophysiological Targets Represent the Winning Therapeu- tic miStrategy? Pharmaceuticals (Basel). 2020;13(11):411. DOI:10.3390/ph13110411. PMID: 33266440 4. Savva M, Papadopoulos NG, Gregoriou S, et al. Recent Advance- ments in the Atopic Dermatitis Mechanism. FBL. 2024;29(2):84. DOI:10.31083/j.fbl2902084 5. Weidinger S, Novak N. Atopic dermatitis. The Lancet. 2016;387(10023):1109-1122. DOI:10.1016/S0140-6736(15) 00149-X 6. O’Sullivan RL, Lipper G, Lerner EA. The Neuro- Immuno-Cutaneous-Endocrine Network: Relationship of Mind and Skin. Archives of Dermatology. 1998;134(11): 1431-1435. DOI:10.1001/archderm.134.11.1431 7. Makowska K, Nowaczyk J, Blicharz L, et al. Immunopathogen- esis of Atopic Dermatitis: Focus on Interleukins as Disease Driv- ers and Therapeutic Targets for Novel Treatments. Int J Mol Sci. 2023;24(1):781. DOI:10.3390/ijms24010781. PMID: 36614224 8. Steinhoff M, Ahmad F, Pandey A, et al. Neuroimmune com- munication regulating pruritus in atopic dermatitis. Journal of Allergy and Clinical Immunology. 2022;149(6):1875-1898. DOI:10.1016/j.jaci.2022.03.010 9. Lee SY, Lee E, Park YM, Hong SJ. Microbiome in the Gut- Skin Axis in Atopic Dermatitis. Allergy Asthma Immunol Res. 2018;10(4):354-362. DOI:10.4168/aair.2018.10.4.354. PMID: 29949831 10. Brunner PM, Guttman-Yassky E, Leung DYM. The Immunology of AD and its Reversibility with Broad Spectrum and Targeted Additionally, the skin has developed a local HPA axis, which functions similarly to the central system. By producing CRH, ACTH, and cortisol independently, this peripheral axis en- ables a rapid response to stress, crucial for the skin’s role in defense against external stressors [32]. In the context of AD, the regulatory function of both the central and local HPA axis is disrupted, exacerbating the vicious cycle of the disease. Chronic stress from physi- cal discomfort, psychological challenges, and environmental triggers further impairs the HPA axis function [33-35]. This leads to dysfunctional cortisol signaling, which fails to sup- press systemic inflammation and contributes to the barrier disruption [32,36]. The resulting compromised barrier per- petuates the underlying AD pathophysiology, underscoring the complexity of this disease. Conclusion The pathophysiology of AD reveals its multifactorial nature and is best understood through the SINGE network, which includes elements such as skin barrier dysfunction, immune dysregulation, neuropeptide involvement, gut microbiota contributions, and the endocrine stress axes. While each component uniquely contributes to the disease, examining them as a whole highlights their interdependent and syner- gistic impact, providing a more comprehensive understand- ing of AD and informing therapeutic targets. Current therapies for AD typically target individual el- ements of the SINGE network. Preventative measures in- clude trigger avoidance, moisturizer use, and gentle bathing [2,37,38]. Other common treatments include topical corti- costeroids, phosphodiesterase inhibitors, and calcineurin in- hibitors for flares as well as ultraviolet phototherapy and systemic immunomodulators for severe presentations [2,38]. Systemic treatment for AD includes biologic agents such as dupilumab, which inhibits both IL-4 and IL-13, and traloki- numab, which targets IL-13. Oral Janus kinase (JAK) inhib- itors have also recently been approved for treatment of AD. Although these therapies significantly improve symptoms, their variable response rates and potential immune-related risks, including susceptibility to infections, present chal- lenges for both patients and clinicians [39,40]. Given the multifactorial nature of AD, a more integra- tive approach to treatment should be explored to compre- hensively address the disease. Emerging treatments offer promising therapeutic approaches by leveraging the in- terconnected SINGE network components. For instance, research on gut microbiome modulation with probiotics, postbiotics, and dietary interventions has suggested po- tential in such agents at restoring immune balance and en- hancing barrier integrity in AD [28,40]. Additionally, agents Review | Dermatol Pract Concept. 2025;15(4):5329 7 26. Yosipovitch G, Berger T, Fassett MS. Neuroimmune interactions in chronic itch of atopic dermatitis. Journal of the European Academy of Dermatology and Venereology. 2019;34(2):239. DOI:10.1111/jdv.15973. PMID: 31566796 27. Symons FJ, Wendelschafer-Crabb G, Kennedy W, Hardrict R, Dahl N, Bodfish JW. Evidence of altered epidermal nerve fi- ber morphology in adults with self-injurious behavior and neurodevelopmental disorders. Pain. 2007;134(1-2):232. DOI:10.1016/j.pain.2007.07.022. PMID: 17850969 28. Tominaga M, Takamori K. Peripheral itch sensitization in atopic dermatitis. Allergology International. 2022;71(3):265-277. DOI:10.1016/j.alit.2022.04.003 29. Gaspar NK, Aidé MK. Atopic dermatitis: allergic dermatitis or neuroimmune dermatitis? Anais Brasileiros de Dermatolo- gia. 2016;91(4):479. DOI:10.1590/abd1806-4841.20164211. PMID: 27579744 30. Sadowsky RL, Sulejmani P, Lio PA. Atopic Dermatitis: Beyond the Skin and Into the Gut. J Clin Med. 2023;12(17):5534. DOI:10.3390/jcm12175534. PMID: 37685600 31. Paz M, Lio P. Postbiotics and Atopic Dermatitis: Aim- ing to Modulate the Gut-Skin Axis. Journal of Integrative Dermatology. Published online June 25, 2024. Accessed August 18, 2024. https://www.jintegrativederm.org/arti- cle/120208-postbiotics-and-atopic-dermatitis-aiming-to-mod- ulate-the-gut-skin-axis 32. Markowiak-Kopeć P, Śliżewska K. The Effect of Probiotics on the Production of Short-Chain Fatty Acids by Human Intesti- nal Microbiome. Nutrients. 2020;12(4):1107. DOI:10.3390 /nu12041107. PMID: 32316181 33. Mousa WK, Chehadeh F, Husband S. Microbial dysbiosis in the gut drives systemic autoimmune diseases. Front Immunol. 2022;13:906258. DOI:10.3389/fimmu.2022.906258. PMID: 36341463 34. Terao M, Katayama I. Local cortisol/corticosterone activa- tion in skin physiology and pathology. Journal of Dermato- logical Science. 2016;84(1):11-16. DOI:10.1016/j.jdermsci .2016.06.014 35. Chen Y, Lyga J. Brain-Skin Connection: Stress, Inflamma- tion and Skin Aging. Inflammation & Allergy Drug Targets. 2014;13(3):177. DOI:10.2174/1871528113666140522104422. PMID: 24853682 36. Lin TK, Zhong L, Santiago JL. Association between Stress and the HPA Axis in the Atopic Dermatitis. International Jour- nal of Molecular Sciences. 2017;18(10):2131. DOI:10.3390 /ijms18102131. PMID: 29023418 37. Suárez AL, Feramisco JD, Koo J, Steinhoff M. Psychoneuro- immunology of Psychological Stress and Atopic Dermatitis: Pathophysiologic and Therapeutic Updates. Acta dermato-vene- reologica. 2012;92(1):7. DOI:10.2340/00015555-1188. PMID: 22101513 38. Begolka WS, Chovatiya R, Thibau IJ, Silverberg JI. Financial Burden of Atopic Dermatitis Out-of-Pocket Health Care Ex- penses in the United States. Dermatitis. 2020;32(1 Suppl):S62. DOI:10.1097/DER.0000000000000715. PMID: 33323748 39. Courtney A, Su JC. The Psychology of Atopic Dermatitis. Journal of Clinical Medicine. 2024;13(6):1602. DOI:10.3390 /jcm13061602 40. Kim BJ, Lee NR, Lee CH, et al. Increased Expression of 11β-Hy- droxysteroid Dehydrogenase Type 1 Contributes to Epidermal Permeability Barrier Dysfunction in Aged Skin. International Therapies. J Allergy Clin Immunol. 2017;139(4 Suppl):S65-S76. DOI:10.1016/j.jaci.2017.01.011. PMID: 28390479 11. Sims JT, Chang CY, Higgs RE, et al. Insights into adult atopic dermatitis heterogeneity derived from circulating biomarker profiling in patients with moderate-to-severe disease. Experi- mental Dermatology. 2021;30(11):1650-1661. DOI:10.1111 /exd.14389 12. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. Journal of Allergy and Clinical Immunology. 2019;143(1):1-11. DOI:10.1016/j.jaci.2018.10.032. PMID: 30612663 13. Hawerkamp HC, Fahy CMR, Fallon PG, Schwartz C. Break on through: The role of innate immunity and barrier defence in atopic dermatitis and psoriasis. Skin Health Dis. 2022;2(2):e99. DOI:10.1002/ski2.99. PMID: 35677926 14. Quaresma JAS. Organization of the Skin Immune System and Compartmentalized Immune Responses in Infectious Diseases. Clin Microbiol Rev. 2019;32(4):e00034-18. DOI:10.1128 /CMR.00034-18. PMID: 31366611 15. Nguyen AV, Soulika AM. The Dynamics of the Skin’s Im- mune System. Int J Mol Sci. 2019;20(8):1811. DOI:10.3390 /ijms20081811. PMID: 31013709 16. Sun N, Ogulur I, Mitamura Y, et al. The epithelial barrier the- ory and its associated diseases. Allergy. n/a(n/a). DOI:10.1111 /all.16318 17. Kim BE, Leung DY. Significance of Skin Barrier Dysfunction in Atopic Dermatitis. Allergy, Asthma & Immunology Research. 2018;10(3):207. DOI:10.4168/aair.2018.10.3.207. PMID: 29676067 18. Çetinarslan T, Kümper L, Fölster-Holst R. The immunolog- ical and structural epidermal barrier dysfunction and skin mi- crobiome in atopic dermatitis-an update. Front Mol Biosci. 2023;10:1159404. DOI:10.3389/fmolb.2023.1159404 19. Kim J, Kim BE, Leung DYM. Pathophysiology of atopic der- matitis: Clinical implications. Allergy and Asthma Proceed- ings. 2019;40(2):84. DOI:10.2500/aap.2019.40.4202. PMID: 30819278 20. Liu AW, Gillis JE, Sumpter TL, Kaplan DH. Neuroimmune In- teractions in Atopic and Allergic Contact Dermatitis. The Jour- nal of allergy and clinical immunology. 2023;151(5):1169. DOI:10.1016/j.jaci.2023.03.013. PMID: 37149370 21. Santamaria-Babí LF. Atopic Dermatitis Pathogenesis: Lessons From Immunology. Dermatology Practical & Conceptual. 2022;12(1):e2022152. DOI:10.5826/dpc.1201a152. PMID: 35223190 22. Legat FJ. Itch in Atopic Dermatitis – What Is New? Frontiers in Medicine. 2021;8:644760. DOI:10.3389/fmed.2021.644760. PMID: 34026782 23. Hülpüsch C, Rohayem R, Reiger M, Traidl-Hoffmann C. Explor- ing the skin microbiome in atopic dermatitis pathogenesis and disease modification. Journal of Allergy and Clinical Immunol- ogy. 2024;154(1):31-41. DOI:10.1016/j.jaci.2024.04.029 24. Boguniewicz M, Leung DY. Atopic Dermatitis: A Disease of Altered Skin Barrier and Immune Dysregulation. Immu- nol Rev. 2011;242(1):233-246. DOI:10.1111/j.1600-065X. 2011.01027.x. PMID: 21682749 25. Shirley SN, Watson AE, Yusuf N. Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology. In- ternational Journal of Molecular Sciences. 2024;25(18):10152. DOI:10.3390/ijms251810152. PMID: 39337637 8 Review | Dermatol Pract Concept. 2025;15(4):5329 45. Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the Neurokinin Receptor 1 with Aprepitant: A Novel Antipruritic Strategy. PLoS One. 2010;5(6):e10968. DOI:10.1371/journal.pone.0010968. PMID: 20532044 46. Müller S, Maintz L, Bieber T. Treatment of atopic dermatitis: Re- cently approved drugs and advanced clinical development pro- grams. Allergy. 2024;79(6):1501-1515. DOI:10.1111/all.16009 47. Paz M, Lio P. Figure 1. The NICE System and Gut-Skin Axis. Created in BioRender. https://BioRender.com/m74v423. 48. Paz M, Lio P. Skin-Immune-Neuro-Gastro-Endocrine (SINGE) System: Lighting the Fire on AD Research. Created in BioRender. https://BioRender.com/o95m463 49. Paz M, Lio P. Figure 3. Pathophysiology of Atopic Dermatitis. Created in BioRender. https://BioRender.com/j21v81. 50. Paz M, Lio P. Figure 4. The Itch-Scratch Cycle. Created in BioRender. https://BioRender.com/u93x140. Journal of Molecular Sciences. 2021;22(11):5750. DOI:10.3390 /ijms22115750. PMID: 34072239 41. Frazier W, Bhardwaj N. Atopic Dermatitis: Diagnosis and Treat- ment. afp. 2020;101(10):590-598. 42. Lugović-Mihić L, Meštrović-Štefekov J, Potočnjak I, et al. Atopic Dermatitis: Disease Features, Therapeutic Options, and a Multidisciplinary Approach. Life (Basel). 2023;13(6):1419. DOI:10.3390/life13061419. PMID: 37374201 43. Davari DR, Nieman EL, McShane DB, Morrell DS. Current Perspectives on the Systemic Management of Atopic Dermatitis. J Asthma Allergy. 2021;14:595-607. DOI:10.2147/JAA. S287638. PMID: 34103945 44. Kim YJ, Granstein RD. Roles of calcitonin gene-related pep- tide in the skin, and other physiological and pathophysiologi- cal functions. Brain Behav Immun Health. 2021;18:100361. DOI:10.1016/j.bbih.2021.100361. PMID: 34746878