Evaluating in-vitro sensitive skin syndrome: from inflammation pathways to cutting-edge models via ZOOM #34

It is defined by unpleasant sensations such as stinging, burning, itching, tingling, or pain in response to everyday stimuli that are normally well tolerated ⁽¹⁾. And may overlap with features seen in common skin inflammatory diseases such as atopic dermatitis and psoriasis. Physical factors such as UV radiation, temperature changes, or mechanical stress, chemical exposures like cosmetics, water, and pollution are all known contributors. Among these, cosmetic products are frequently cited as triggers, underlining the importance of evaluating the tolerance of ingredients and formulations specifically for sensitive skin.

While 2D co-culture systems are simple and cost-effective, they fail to recapitulate 3D cellular interactions or the skin barrier function. Consequently, 3D approaches offer more accurately model physiological and pathological skin conditions. Technological advances have made it possible to recreate and study these mechanisms of sensitive skin using in vitro models. Currently, the disruption of the barrier function, immune activation and neurogenic inflammation have been identified as the three mechanisms potentially involved in the physiology of sensitive skin. In order to develop effective cosmetics or active ingredients, it is crucial to have relevant and predictive in vitro models. 3D reconstructed human epidermis and full-skin equivalents with varying degrees of physiological complexity are commonly used to examine barrier integrity whether there are bioprinted or not, non-vascularized or vascularized ⁽²⁾. While more complex in vitro models have been investigated to recapitulate the immunological functions of the skin to model inflammatory skin diseases such as atopic dermatitis and serve as robust platforms for in vitro assays. ⁽³⁾

Particular interest is being paid to microfluidic models commonly known as skin-on-a-chip, which more closely reproduce in vivo physiological conditions, particularly cytokine gradients and spatially organized cellular interactions. These technological advances offer promising prospects for screening ingredients and gaining a better understanding of their mechanisms of action on the skin ^(3,4).

Moreover, since the importance of neuro-immune-cutaneous interactions in the inflammatory response has emerged, innervated models incorporating sensory neurons derived from induced pluripotent stem cells have been developed making it possible to investigate the neuronal contribution to sensitive skin. These innervated models provide a unique opportunity to study how sensory neurons release neuropeptides under stimulation, driving inflammation and discomfort, and how active ingredients may modulate these pathways.

The mechanisms of neurogenic skin inflammation represent a process in which the peripheral nervous system plays a central role in initiating and maintaining inflammatory responses ⁽⁴⁾. Thus, sensory nerve fibers, in response to mechanical, thermal or chemical stimuli, release neuropeptides such as substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A. These mediators act on resident skin cells (keratinocytes, mast cells, dendritic cells) and immune cells, amplifying the inflammatory response and contributing to pathologies such as psoriasis, atopic dermatitis and urticaria ⁽⁵⁾.

To assess the soothing or protective potential of active ingredients, in vitro assays typically expose reconstructed skin or cell cultures to controlled irritants such as pollutants or UV light. The work of testing laboratories today focuses on modelling skin inflammation in order to reproduce in a standardized manner this complex process involving cellular and molecular interactions between keratinocytes, fibroblasts, immune cells and the extracellular matrix.

A reduction or normalization of inflammatory markers may indicate a protective effect. Core mediators include cytokines such as IL-1α/β, IL-6, TNF-α, and IFN-γ, as well as prostaglandin E2^(6-7). The Th2/Th17 axis also plays an important role, with IL-4, IL-13, IL-17, IL-22, IL-23, and IL-31 contributing to allergic inflammation, pruritus, and conditions such as atopic dermatitis and psoriasis ⁽³⁾.

Additional markers include IL-8 and GM-CSF, which regulate immune cell recruitment and activation. Barrier- and structure-related molecules such as filaggrin, cytokeratin-17, and CD44 provide further insights into epidermal integrity under stress. In more advanced studies, molecules such as TSLP, matrix metalloproteinases, sirtuin-1, and hyaluronic acid fragments are also assessed to capture broader aspects of the inflammatory cascade. The syndrome of Sensitive Skin is often associated with small fibre neuropathies involving receptors such as TRPV1 (transient receptor potential vanilloid 1), which respond to heat, acidic pH, capsaicin or histamine ⁽⁴⁾.

In vitro models provide effective tools to study the complex interplay between barrier impairment, neurogenic inflammation, and immune responses. They enable researchers and product developers to assess how ingredients and formulations influence skin sensitivity, thereby supporting the design of safer and more effective solutions for individuals with sensitive skin.

REFERENCES

1. Polena H, Fontbonne A, Abric E, Lecerf G, Chavagnac-Bonneville M, Moga A, Ardiet N, Trompezinski S, Sayag M. Management of triggering factor effects in sensitive skin syndrome with a dermo-cosmetic product. J Cosmet Dermatol. 2024;23(12):4325-4333. doi: 10.1111/jocd.16529
2. Liu X, Michael S, Bharti K, Ferrer M, Song MJ. A biofabricated vascularized skin model of atopic dermatitis for preclinical studies.Biofabrication. 2020 Apr 9;12(3):035002. 
3. Moon S, Hyun Kim D, U Shin J. In Vitro Models Mimicking Immune Response in the Skin. Yonsei Med J. 2021; 62(11):969-980.
4. Guichard A, Remoué N, Honegger T. In Vitro Sensitive Skin Models: Review of the Standard Methods and Introduction to a New Disruptive Technology. Cosmetics. 2022; 9(4):67.
5. Choi JE, Di Nardo A. Skin neurogenic inflammation. Semin Immunopathol. 2018;40(3):249-259.
6. Boarder E, Rumberger B, Howell MD. Modeling Skin Inflammation Using Human In Vitro Models. Curr Protoc. 2021;1(3):e72.
7. He BW, Wang FF, Qu LP. Anti-Inflammatory and Antioxidant Properties of Physalis alkekengi L. Extracts In Vitro and In Vivo: Potential Application for Skin Care. Evid Based Complement Alternat Med. 2022 ; 19;2022:7579572. doi: 10.1155/2022/7579572.