Skin Barrier Dysfunction in Contact and Atopic Dermatitis: A Comparative Review

Abstract

The epidermis, the outermost layer of the skin, consists of 5 distinct layers, with the stratum corneum (SC) serving as the primary barrier. Disruption of skin barrier leads to inflammatory skin conditions, including irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and atopic dermatitis (AD). ICD arises from direct damage to the SC by irritants, while ACD is mediated by a type IV hypersensitivity. AD is characterized by chronic inflammation and genetic defects that compromise barrier integrity. Accordingly, strategies aimed at barrier restoration, such as the use of ceramide-based moisturizers, are key therapeutic approaches. Recent guidelines emphasize the importance of barrier-enhancing interventions, yet compliance remains a challenge in occupational settings. This review explores the implications of skin barrier dysfunction in contact dermatitis and AD, highlighting emerging therapeutic strategies aimed at restoring barrier function and reducing disease burden.

Graphical Abstract

INTRODUCTION

The epidermis, the outermost layer of the skin, is composed of 5 distinct layers, among which the stratum corneum (SC) plays a crucial role as the primary skin barrier.¹ The SC structure is often described using the “brick and mortar” model, where protein-enriched corneocytes act as “bricks” embedded in a lipid-rich intercellular matrix, the “mortar.”²,³ This matrix, mainly composed of ceramides, free fatty acids (FFAs), and cholesterol (CHOL), forms a highly organized lamellar structure essential for preventing water loss and blocking external substances. The structural integrity of corneocytes is reinforced by proteins like filaggrin, which also produces natural moisturizing factors (NMFs) crucial for skin hydration.⁴ The homeostasis of SC lipids is maintained by a complicated network of metabolic enzymes (e.g., fatty acid elongase, fatty acid desaturases, ceramide synthase, and ceramidases); consequently, dysregulation of these pathways perturbs the lamellar organization and, ultimately, results in disrupted skin barrier function.⁵ In particular, acylceramides are indispensable for skin barrier formation.¹,³,⁵ Among various enzymes involved in the catabolic pathway of acylceramides, SDR9C7 (Short-Chain Dehydrogenase/Reductase Family 9C Member 7) catalyzes a critical oxidation step of ω-hydroxyceramide to ω-oxo-ceramide,⁶ which then undergoes esterification with linoleic acid, forming acylceramide (ceramide EOS).³,⁵ Recent studies have shown that biallelic variants in SDR9C7 underlie autosomal recessive congenital ichthyosis, since SDR9C7 catalyzes a critical dehydrogenation step in acylceramide processing required for corneocyte lipid envelope (CLE) formation.⁶ Consistent with this result, SDR9C7 deficiency impairs epidermal barrier function and is associated with abnormal CE lipidation and immature barrier assembly.⁶,⁷

Beyond the epidermal permeability barrier, the cutaneous defense system is multifaceted, incorporating chemical, microbial, and immune components. The chemical barrier is maintained by the NMFs and acidic surface pH, which are important for providing the proper conditions for the diverse enzymes involved in barrier homeostasis. Notably, recent findings have revealed that the acidic pH at the skin surface does not form a simple gradient, but consists of 3 distinct, stepwise pH zones within the SC, adding a new layer of complexity to current understanding.⁸ The immune barrier, mainly composed of immune cells like Langerhans cells and T cells, provides constant surveillance against pathogens and antigens.⁹

Disruption of any component of this intricate barrier system is a key pathogenic event in most inflammatory skin diseases, including irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and atopic dermatitis (AD). A deeper understanding of the structure and function of the skin barrier is crucial for developing effective treatments. This review will explore the distinct mechanisms underlying skin barrier disruption in ICD, ACD, and AD, discuss key biomarkers for their differentiation, and summarize therapeutic strategies focused on the barrier function restoration.

CLINICAL FEATURES AND GENERAL PATHOGENESIS OF CONTACT DERMATITIS (CD) AND AD

CD can be classified into 2 primary subtypes: ICD and ACD. These conditions, while distinct in their etiology, share significant pathophysiological overlaps, particularly in skin barrier dysfunction and immune activation.¹⁰ Due to the similarities in clinical features and barrier-related pathology, it is important to distinguish CD from AD.

ICD, ACD, and AD are generally described as eczematous dermatitis based on their clinical features, but they should be carefully distinguished by the triggering factors, immune responses, and resulting clinical presentations, which is crucial for accurate diagnosis and management. The most noticeable difference is the initial trigger and the pace of the immune response. ICD is directly elicited by cytotoxic damage to the skin and characterized by a rapid innate immune response, which explains the prompt onset (minutes to hours) of symptoms of erythema and scaling, strictly to the contact site.¹¹,¹² In contrast, ACD is an adaptive, T-cell-mediated process that requires prior sensitization; upon re-exposure (elicitation phase), symptoms typically appear after a 24–72 hour delay as memory T cells drive inflammation.¹² Consistently, barrier disruption lowers the threshold for allergen penetration and facilitates cutaneous sensitization during the induction phase of ACD.¹³ While barrier impairment can aggravate or intensify disease in both ICD and ACD, immediate management prioritizes trigger avoidance and inflammation control, with barrier repair serving as an important adjunct to reduce recurrence and expedite recovery.

In AD, however, inherent barrier defects—driven by predisposed genetic factors such as filaggrin mutations and modulated by environmental exposures—are primary pathophysiological drivers of disease initiation and aggravation. The resulting chronic vulnerability sustains persistent immune dysregulation dominated by a Th2 response. Th2 cytokines, including interleukin-4 (IL-4) and IL-13, not only mediate acute inflammation triggered by stimuli but also underpin the chronic relapsing–remitting course of AD; IL-31 is directly linked to intense pruritus and contributes to lichenification in flexural areas due to chronic scratching.¹²,¹³,¹⁴ Notably, even acute mechanical barrier disruption can upregulate epidermal Th2-attracting chemokines (e.g., TARC/CCL17, MDC/CCL22) and elicit a late-phase–like reaction, supporting the concept that scratching-related injury transiently amplifies Th2-skewed inflammation in AD.¹⁵ Consistently, tape-strip studies of AD skin capture Th2-centered immune/barrier signatures (including CCL17 and IL-13) that correlate with disease activity, pruritus, and trans-epidermal water loss (TEWL), and that help differentiate AD from non-AD conditions.¹⁶,¹⁷

These interconnected clinical and pathogenic distinctions are summarized comprehensively in Table 1.

Table 1. Comparative pathogenesis of ICD, ACD, and AD.

Feature	ICD	ACD	AD	Key references
Primary cause	Direct toxicity from the external irritants (e.g., surfactants, solvents)	Type IV delayed-hypersensitivity reaction to a specific allergen (hapten)	Genetic predisposition leading to inherent structural and functional barrier defects	11,14,18,19
Primary barrier defect	Acquired and acute; direct damage to stratum corneum lipids and corneocytes	Acquired and secondary; inflammation-driven barrier damage follows sensitization	Inherent and chronic; primarily due to filaggrin mutations and deficient ceramide synthesis	12,14,20,21
Dominant immune pathway	Innate immunity	Adaptive immunity (T-cell-mediated; biphasic with sensitization and elicitation phases)	Chronic immune dysregulation (interplay of innate and adaptive immunity)	11,15,18,22
Key immune cells	Keratinocytes, macrophages, neutrophils	Langerhans cells, memory T cells (Th1, Th2, Th17)	Dendritic cells, T cells (Th2 dominant, later Th17/Th22), eosinophils, mast cells	12,15,23,24
Key cytokines & mediators	Alarmins: IL-1α, TSLP; pro-inflammatory cytokines (e.g., TNF-α)	Th2: IL-4, IL-13; Th1/Th17: IFN-γ, IL-17	Alarmins: TSLP, IL-33; Th2: IL-4, IL-13, IL-31; chronic phase: Th17/Th22 cytokines	12,15,21,25,26,27,28
Pathogenic summary	Barrier damage → innate activation (danger signals) → inflammation → further barrier damage	Sensitization → re-exposure → adaptive T-cell activation → inflammation → barrier damage	Genetic defect → barrier dysfunction → allergen/irritant entry → Th2-skewed inflammation → further barrier degradation	11,12,14,27

ICD, irritant contact dermatitis; ACD, allergic contact dermatitis; AD, atopic dermatitis; IL, interleukin; TSLP, thymic stromal lymphopoietin; TNF, tumor necrosis factor; IFN, interferon.

EXTERNAL CONTRIBUTORS TO SKIN BARRIER DAMAGE FOR ICD

The pathogenesis of ICD is closely linked to structural damage to the SC, and external factors affecting the structural property of the SC, including surfactants, solvents, and overhydration, can trigger inflammatory and immune responses that exacerbate ICD symptoms. In experimental models mimicking structural damage, repeated mechanical insults (e.g., repetitive rubbing or tape-stripping surrogates) can be used for removing corneocytes and SC intercellular lipids. An abrupt increase in TEWL, a functional marker for evaluating the epidermal permeability barrier function, represents the disruption of skin barrier function.²⁹ Tape stripping also induces the immediate release of pre-formed IL-1α in epidermis, and expression of Th2-attracting chemokines, which can lower the threshold for irritant and allergic responses.¹⁵,²¹ In occupational contexts, friction often co-occurs with wet work, further aggravating the compromise of the skin barrier.²⁰

Anionic surfactants

It is well known that anionic surfactants, which are commonly used for washing products as detergents, can directly damage the epidermal permeability barrier function through both physical and biochemical mechanisms. As a model compound, research has been focused on the sodium lauryl sulfate (SLS). SLS, a strong surfactant, structurally damages the skin barrier by harming corneocytes, expanding intercellular spaces, and weakening cell junctions.³⁰ It also removes lipids and NMFs from the SC and activates serine proteases like KLK5 and KLK7, further disrupting protein and lipid metabolism.³¹,³² These combined effects, represented by the increased TEWL, facilitate penetration of the irritants and induce SC overhydration, which in turn accelerates ICD pathogenesis and further weakens the skin barrier.³³,³⁴ Notably, inter-individual variation in SLS penetration rates correlates with the degree of barrier impairment and inflammation, underscoring subject-specific susceptibility to irritant challenge.³⁵

SLS exposure has been shown to induce cytoplasmic vacuoles around cell nuclei and expand intercellular spaces, causing structural changes in epidermal keratinocytes. These alterations increase water evaporation and impair skin barrier recovery.³⁰,³³ SLS also resulted in changes in keratinocyte differentiation markers, i.e., involucrin, transglutaminase 1, and filaggrin, at both the mRNA and protein levels, delaying barrier recovery after exposure.³¹ In addition to these effects, SLS inhibits genes involved in sphingolipids metabolism, such as serine palmitoyl transferase-2, sphingomyelin phosphodiesterase-1, and β-glucocerebrosidase. These inhibitions impair epidermal lipid synthesis and weaken barrier function. Moreover, SLS reduces NMF levels, altering SC hydration and keratin fiber organization.³²,³⁶ Studies comparing SLS and acetone on skin barrier disruption revealed that while SLS disrupts SC lipid structure and corneocyte cohesion, acetone selectively extracts SC intercellular lipids without extensive cellular disruption, highlighting the greater potency of SLS in damaging barrier function.³⁰

Overhydration

Prolonged exposure to water and the consequent overhydration of the SC are another important pathophysiological factor for ICD. In real-life terms, this can occur from prolonged occupational wet work, such as in healthcare or cleaning, or from wearing occlusive gloves for several hours. Overhydration not only disrupts the lipid lamellae in SC,³⁷ but is associated with elevated surface pH that sustains serine-protease activity and impairs lipid-processing enzymes.³⁸ This altered pH environment, combined with structural weakening from swelling, further compromises barrier integrity.³⁹ It can also trigger the release of pro-inflammatory cytokines such as IL-1α, IL-1β, and tumor necrosis factor (TNF)-α, which can initiate inflammatory cascades.²¹,³⁸ Consistent with real-world practice, occupational guidelines identify wet work and prolonged occlusion as key modifiable factors of exposure and primary prevention targets.⁴⁰,⁴¹

Alcohol

Alcohols, particularly ethyl alcohol and isopropyl alcohol used in hand sanitizers and cleaning agents, can also exacerbate skin barrier damage by denaturing corneocyte proteins and extracting SC intercellular lipids.⁴² This leads to changes in corneocyte surface topography, a decrease in NMF, and a reduction in SC hydration.³⁹,⁴³ Frequent use of alcohol-based products can elicit skin xerosis, leading to fissuring and further weakening of the barrier, thereby highlighting the increased risk of ICD in occupations requiring frequent hand hygiene.³⁹ These findings underscore the importance of minimizing exposure to harsh irritants and implementing strategies to protect the skin barrier.

SKIN BARRIER BIOMARKERS IN AD AND CDS (ICD AND ACD)

While AD, ICD, and ACD can present with similar clinical features, they exhibit distinct differences in their underlying mechanisms of barrier dysfunction and their resulting biomarker profiles. Understanding these biomarkers is crucial for accurate diagnosis, severity assessment, and monitoring treatment responses. Table 2 summarizes the key alterations and clinical utility of major skin barrier biomarkers across these 3 conditions.

Table 2. A comparative overview of key skin barrier biomarkers in ICD, ACD, and AD.

Biomarker class	Specific biomarker	ICD	ACD	AD	Clinical utility	Key references
Biophysical Parameters	TEWL	↑↑↑ (Acute, sharp increase post-exposure)	↑ (Moderate increase)	↑↑ (Chronic, marked increase)	Quantitative assessment of barrier integrity; treatment efficacy monitoring	9,29
	SC hydration	↓ (Transient decrease by irritants)	↓ (Decreased in inflamed areas)	↓↓ (Chronic decrease)	Evaluation of moisturizer efficacy; correlates with disease severity	9,39
	Skin surface pH	↔︎/↑ (Variable, depends on irritant)	↔︎ (No significant change)	↑ (Alkaline shift > 5.5)	Indicator of acid mantle disruption	9,38
Barrier Lipids	Total ceramides	↓ (Stripped by surfactants/solvents)	↓ (Reduced; abnormalities reported even in nonlesional skin)	↓ (Overall reduction)	Lipid barrier integrity	44,45
	Ceramide subclasses*	↔︎/↓ (Non-specific reduction)	↓ (Long-chain classes [data limited])	↓↓ EOS, NP, NS, AS, AP (esp. very long-chain)	Pathophysiologic insight; AD > ACD	44,46,47
Structural Proteins	FLG	↓ (Secondary to inflammation)	↓ (Secondary to inflammation)	↓↓ (Often due to primary genetic mutations)	Genetic predisposition to AD; differentiation	9,14
	Tight junctions (Claudin-1)	↓ (Disrupted by acute damage)	↓ (Inflammation-mediated)	↓ (Increased permeability)	Epithelial permeability/cohesion	9,34
Hydration Factors	NMFs† (PCA, UCA)	↓ (Stripped/wash-out by irritants)	↓ (Moderately decreased)	↓↓ (Impaired due to FLG deficiency)	SC water-holding capacity; occupational monitoring	9,36,39
Enzymes	Kallikreins (KLK5, 7)	↑ (Activated by surfactants)	↔︎/↑ (Slightly increased)	↑ (Increased activity due to elevated pH)	Abnormal desquamation marker	9,38,48
Immune Markers	Antimicrobial peptides‡	↑ (Non-specific innate response)	↑ (Inflammation-associated)	↔︎/↓ (Low at baseline; ↑↑ during flares/infection)	Innate activation & infection susceptibility	9,49

↑, increase; ↓, decrease; ↔, no significant change or variable; the number of arrows indicates the magnitude of change.

ICD, irritant contact dermatitis; ACD, allergic contact dermatitis; AD, atopic dermatitis; TEWL, trans-epidermal water loss; SC, stratum corneum; FLG, filaggrin; NMF, natural moisturizing factor; PCA, pyrrolidone carboxylic acid; UCA, urocanic acid.

^*Ceramide subclasses include EOS, EOH, NP, NS, AS, AP; ^†NMF key components include PCA and UCA; ^‡AMP examples include Cathelicidin (LL-37) and human β-defensins (hBD-2, hBD-3).

LIPID PROFILE ALTERATIONS IN AD, ACD, AND NORMAL SKIN

Quantitative differences in SC ceramides are a significant distinction between normal, ACD, and AD skin.⁴⁴ While other major lipids, such as triacylglycerols, CHOL, and FFA, show no consistent differences, total ceramide concentrations are significantly lower in AD compared with normal skin.⁴⁵ Although datasets are relatively limited, non-lesional skin in ACD also displays barrier and ceramide abnormalities.⁴⁴ In addition to the decrease in total amounts, changes in class-level ratios—particularly NP/NS, NH/NS, NP/AS, and NH/AS—track barrier status, showing negative correlations with TEWL and positive correlations with capacitance; these relationships, along with anatomic-site and seasonal variability (e.g., cheek in winter vs. summer), are well described in healthy populations.⁵⁰ Given the disease-relevant impact of ceramide chain-length distribution on barrier function, cross-study comparisons should be interpreted with careful consideration of the reported analytical conditions to avoid overgeneralization.⁵¹ Despite these limitations, the most notable difference lies in the fatty-acid chain-length distribution of ceramides. ACD is characterized by a decrease in long-chain ceramides, whereas AD exhibits a more complex change. In AD, while decrease in long-chain ceramides—which can impair the skin barrier integrity—is observed,²³,⁴⁴,⁴⁶ while potential compensatory increases in short-chain ceramide species are also detected.⁴⁴,⁴⁷ Mechanistically, inflammatory cytokines in inflamed skin (e.g., IL-4/IL-13, interferon-γ, and TNF-α) have been also implicated in dysregulating ceramide metabolism, supporting a plausible inflammation–lipid abnormality axis in AD.⁴⁶,⁴⁷ Recent review articles have comprehensively examined the emerging associations between ceramide profiles and skin health.²⁴,⁵¹ Acylceramides (EOS/EOH) and protein-bound ω-hydroxyceramides that form the CLE can serve as indicators of barrier status in population analyses.⁵¹ Higher acylceramides and adequate levels of these protein-bound species are associated with greater skin-surface capacitance—reflecting better hydration—and lower TEWL, whereas higher proportions of short-chain NS/AS classes and reduced CLE-linked species are generally seen with barrier dysfunction.⁵⁰,⁵¹ Moreover, baseline profiles vary by the anatomic sites and seasons, so site-specific sampling and seasonal control are recommended in the study design.⁵⁰ Finally, although class-resolved datasets for ACD remain limited, trials in occupational hand dermatitis and guideline recommendations support the clinical relevance of lipid repletion and regular moisturizer use for improving barrier function within weeks.⁴⁰,⁴¹

CONCLUSION: PREVENTION AND TREATMENT OF CDS BASED ON SKIN BARRIER THEORY

Skin barrier-based strategies underscore the centrality of restoring barrier integrity in CD.¹² Irritants, such as SLS, directly damage the barrier; therefore, irritant avoidance plus barrier restoration is essential to minimize damage and restore function.⁴ Because irritants can trigger danger signals/alarmins and amplify innate immune activation, adjunctive measures that limit this cascade help mitigate downstream inflammation.⁴⁸ In ACD, irritation may precede allergen exposure; therefore, barrier optimization reduces the likelihood of sensitization and flares. Likewise, in AD—where the barrier is intrinsically compromised—robust barrier care lowers the risk of superimposed ICD/ACD and improves overall control.¹²

Focusing on ICD and ACD, Table 3 summarizes clinically relevant, mechanism-aligned interventions that map specific actionable mechanisms to corresponding biomarkers and therapeutic modalities.

Table 3. Barrier-restoration mechanisms mapped to actionable modalities (ICD/ACD).

Mechanism (actionable target)	Primary target(s)	Biomarkers to monitor	Therapeutic modalities (examples)	Best use	Key references
Lipid synthesis enhancement	Ceramide profile (NP/NS, EOS/EOH), lamellar structure	TEWL↓, Capacitance↑, Ceramide profile↑	Ceramide-dominant/physiologic-ratio moisturizers; occlusives; gentle/nonionic cleansers [ICD][ACD]	Primary for ICD, adjuvant for ACD	23,52
Protease inhibition	Kallikreins (KLK5/7), corneodesmosomal integrity	KLK activity↓, TEWL↓	Topical serine protease inhibitors (investigational); acidifying care to indirectly lower KLK [ICD][ACD]	Adjuvant for ICD/ACD	48
pH modulation	Surface pH (≤ 5.5), pH-sensitive lipid-processing enzymes	Surface pH ≤ 5.5, KLK activity↓	Urea 5%–10%, low-% lactic acid, pH-balanced cleansers/emulsions [ICD][ACD]	Primary for ICD, adjuvant for ACD	38,52
Alarmin suppression	TSLP, IL-33, IL-4/13 milieu (where relevant)	TSLP/IL-33 levels↓, clinical inflammation↓	Biologics targeting Th2/alarmins (e.g., anti–IL-4Rα, anti–TSLP); selected cases [ACD]	Selected ACD cases	28
Microbiome support	Microbial diversity, AMPs (LL-37, hBDs)	Microbial diversity↑, AMP levels (normalized)	Pre-/probiotics; microbiome-friendly cleansers/moisturizers [ICD][ACD]	Adjuvant for ICD/ACD	52

↑, increase; ↓, decrease; the number of arrows indicates the magnitude of change.

ICD, irritant contact dermatitis; ACD, allergic contact dermatitis; TEWL, trans-epidermal water loss; TSLP, thymic stromal lymphopoietin; IL, interleukin; AMP, antimicrobial peptide.

As highlighted in Table 3, the cornerstone of these strategies is the appropriate selection of moisturizers and cleansers.⁵²,⁵³ Effective moisturizers should contain ingredients such as ceramides, glycerin, urea, dimethicone, and petrolatum, while cleansers should favor nonionic surfactants and maintain hydration and pH balance.⁵² Before implementing barrier-restorative strategies in occupational hand dermatitis, accurate diagnosis for either irritant or allergic CD with clinical evaluation and patch testing is crucial.⁵⁴ For the prevention in occupational settings, regular use of moisturizers and appropriate protective equipment is recommended—supported by a Cochrane review showing protective effects of moisturizers (alone or with barrier creams) and by ESCD guidelines endorsing moisturizers for prevention and treatment.⁴⁰,⁴¹ Consistent management practices, education, and behavioral interventions are essential for preventing barrier damage and promoting long-term skin health; however, workplace compliance remains low, underscoring the need for the systematic dissemination of risk awareness and preventive measures.