Skin-Immune-Neuro-Gastro-Endocrine (SINGE) System: Lighting the Fire on Atopic Dermatitis Research

Abstract

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by pruritic, 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 clinical 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 to AD symptoms by perpetuating the itch-scratch cycle. Neuroendocrine factors amplify the inflammatory dysregulation, particularly through endocrine involvement involving cortisol signaling in the hypothalamic-pituitary-adrenal (HPA) axis and the paradoxical inflammatory effects on the skin barrier. Together, these intertwined pathways perpetuate the chronic inflammation and skin barrier dysfunction 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.

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 synthesizes both frameworks to provide a more comprehensive understanding of AD pathogenesis.

Figure 2

The Skin-Immune-Neuro-Gastro-Endocrine (SINGE) Network in atopic dermatitis (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.

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).

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, further fueling the cycle.