Skin Barrier Dysfunction in Acne Vulgaris: Pathogenesis and Therapeutic Approaches

Introduction

Acne vulgaris, commonly referred to as “acne”, is a chronic inflammatory condition that primarily affects the hair follicle-sebaceous gland unit. It is most prevalent during adolescence, with an incidence as high as 93% among teenagers, making it the most common skin disorder globally [1]. Acne often leads to post-inflammatory erythema and hyperpigmentation. Studies indicate that 37% of patients with acne develop skin sensitivity, and 3% to 7% can experience scarring, significantly affecting their appearance and overall well-being [2]. The pathogenesis of acne vulgaris is closely linked to androgen-induced sebaceous gland enlargement, excessive sebum production, abnormal keratinization of the follicular duct, microbial proliferation (eg, Cutibacterium acnes), and inflammatory immune responses [3–5] (Figure 1). Androgens trigger sebaceous gland hyperplasia and increased sebum secretion, leading to hyperkeratosis at the follicular duct opening and causing sebum and keratinocytes to accumulate within the follicle, forming whiteheads. The oxidation of sebum combined with surface debris results in blackhead formation. The sebum accumulation creates a nutrient-rich environment for microorganisms, such as Cutibacterium acnes, Staphylococcus aureus, and Malassezia species, promoting their proliferation. These microorganisms produce enzymes that break down sebum into free fatty acids, further stimulating follicular inflammation, resulting in papules and pustules. As the inflammatory response intensifies, the follicular wall can rupture, allowing lipids, microorganisms, and other materials to penetrate deeper into the dermis, leading to folliculitis and perifolliculitis, which manifest as deep cysts and nodules. Genetic factors also play a significant role in severe acne [6], while factors such as obesity, high-sugar, high-fat, or dairy-rich diets, improper skincare, makeup, sun exposure, stress, and lack of sleep are known to trigger or exacerbate the condition [7].

The skin, the largest organ of the human body, serves as a physical, chemical, immune, and microbial barrier against external environmental factors [8]. The physical barrier, also known as the permeability or mechanical barrier, consists of keratinocytes connected by proteins and a balanced ratio of lipids (ceramide: free fatty acids: cholesterol=3: 1: 1), forming the first line of defense against external aggressions [9]. The chemical barrier is composed of lipids and acids secreted by the epidermis and microbes, maintaining a low pH to inhibit pathogenic microbial growth and enhance skin immunity [8,10]. The immune barrier refers to the innate and adaptive immunity stimulated by the skin microbiome, such as Streptococcus epidermidis activating gδ T cells and upregulating perforin-2, to regulate the innate immune system [11], and Candida albicans stimulating an auxiliary T (Th) 17 or Th21 immune response in the skin, to prevent skin or systemic infections [12]. The microbial barrier involves microbe-microbe interactions, preventing the invasion, colonization, and infection of pathogenic or opportunistic microbes, thus maintaining microbial survival, niches, and pathways for nutrient acquisition [13]. The skin barrier protects the body from harmful external factors, but it can also be damaged by these same factors. In 2017, the European dermatologists defined the “acne exposome” as the sum of all environmental factors that influence the onset, duration, and severity of acne. These factors interact with the skin barrier, sebaceous glands, innate immunity, and skin microbiome, contributing to the development and progression of acne [14].

Recent studies have shown that patients with acne vulgaris often exhibit compromised skin barriers. Evidence suggests that these patients experience significant increases in transepidermal water loss (TEWL), pH levels, sebum production, porphyrins, and erythema, along with decreased microbial diversity, all of which correlate with the severity of the condition and the integrity of the skin barrier [15]. Alterations in barrier structure molecules and connecting proteins, such as claudin-1 (CLDN1), filaggrin, keratin 1, and desmoglein 1 (DSG1), have been observed in the epidermis of patients with acne, with changes in their spatial expression patterns [16]. For instance, CLDN1, typically expressed in the superficial layers of normal skin, is confined to the basal and granular layers in patients with acne, with complete absence in the stratum corneum. Moreover, certain sebum components have been found to regulate the expression of proteins related to barrier function [16]. This suggests that skin barrier impairment in acne vulgaris extends beyond the stratum corneum (Figure 2).

This review provides a comprehensive overview of the mechanisms by which the skin barrier is compromised in acne vulgaris and discusses methods for its repair, with the goal of enhancing the understanding of skin barrier function and its relationship to acne treatment. It seeks to inspire new avenues for basic research and clinical management of acne vulgaris.

Mechanisms of Skin Barrier Impairment in Acne Vulgaris

SEBACEOUS GLANDS AND THE SKIN BARRIER:

Lipids secreted by sebaceous glands constitute 90% of the surface lipids on the skin of adolescents and adults, playing a key role in maintaining skin barrier integrity and innate immune processes around hair follicles and in the dermis. Research indicates that areas rich in sebaceous glands exhibit lower expressions of DSG1, corneodesmosin, occludin, and CLDN1, suggesting weaker physical barrier characteristics in these regions [17]. Additionally, in patients with acne vulgaris, androgen-induced hyperplasia of sebaceous glands and massive lipid secretion [18], along with changes in lipid composition such as increased levels of squalene peroxide, wax esters, free fatty acids, unsaturated fatty acids, and decreased linoleic acid [19], all contribute to the disruption of the skin barrier.

INFLAMMATION AND THE SKIN BARRIER:

Acne vulgaris is a chronic inflammatory skin disease, with inflammation present throughout its course. Inflammatory cytokines, including interleukins (IL-1β, IL-17, IL-6), transforming growth factor β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and type I insulin-like growth factor (IGF), are upregulated in acne lesions [20,21]. The IL-1 receptor expressed on the membrane surface can transduce the IL-1β signal into intracellular signaling, thereby activating the NF-κB and AP-1 signaling pathways [22]. TNF-α can also increase the activity of NF-κB and AP-1 by stimulating intercellular adhesion molecule 1. These activated pathways promote the production of inflammatory cytokines in effector cells. Pro-inflammatory cytokines, such as IFN-γ and TNF-α, can disrupt the epithelial barrier in a manner independent of apoptosis. This process can occur by impairing the mucosal barrier function through the apical junctional complex and altering the lipid composition within the tight junction membrane microdomains [23,24]. IGF-1 can also affect the skin barrier by regulating sebaceous gland function and keratinocyte differentiation [25]. These cytokines not only cause keratinocytes to swell and widen intercellular spaces, weakening the skin barrier, but also disrupt the barrier by altering the function of sebaceous glands and keratinocytes.

MICROBIOME AND THE SKIN BARRIER:

The skin microbiome, comprising bacteria, fungi, viruses, and their surrounding environment, coexists with the skin barrier and influences it through physical, chemical, and immune mechanisms [26]. In mouse models of skin injury, epidermal commensal microbes activate the aryl hydrocarbon receptor in keratinocytes, promoting epidermal differentiation and maintaining barrier integrity [27]. Epidermal commensal Streptococcus increases skin ceramide levels in a manner fully dependent on sphingomyelinase, preventing skin moisture loss [28]. Cutibacterium acnes, a skin-resident bacterium, enhances the skin barrier by affecting tight junction proteins. However, as Cutibacterium acnes proliferates, it exhibits opposite biological characteristics [29], stimulating IGF expression and activating Toll-like receptor (TLR)-2 to induce monocytes to produce TNF and IL [30], verifying the important role of the skin microbiome in maintaining the skin barrier.

EXPOSOME AND THE SKIN BARRIER:

Acne-related exposome factors affecting the skin barrier can be grouped into 7 categories: ultraviolet (UV) radiation, nutrition, iatrogenic damage, occupational factors (including cosmetics), pollutants, climate, and psychosocial factors [14,31] (Figure 3).

ULTRAVIOLET RADIATION:

Numerous studies have shown that UV exposure damages the skin barrier [32], making it more susceptible to irritants and harmful factors, such as UV radiation, chemicals, and microorganisms. The UV spectrum (100–400 nm) is divided into 3 bands: UVA (320–400 nm), UVB (280–320 nm), and UVC (100–280 nm). UVC is almost entirely absorbed by the ozone layer and does not reach the Earth’s surface. UVB, with its higher energy, can directly damage the epidermis, while UVA penetrates deeper into the dermis, degrading elastin and collagen fibers, leading to skin aging [33]. The impact of UV radiation on the skin barrier primarily involves the following aspects [31,34,35]:

STRATUM CORNEUM DAMAGE: The stratum corneum, the outermost layer of the skin, is essential for preventing water loss and protecting against external harmful agents. UV radiation, particularly UVB, can directly damage this layer, causing abnormal differentiation of keratinocytes. This leads to a thinner stratum corneum or structural abnormalities within keratinocytes, thereby weakening the physical protective function of the skin barrier [32].

DNA DAMAGE: UV radiation induces photochemical damage to the DNA in skin cells, resulting in the formation of cyclobutane pyrimidine dimers and other DNA lesions. This damage not only elevates the risk of skin cancer but also triggers cell apoptosis and inflammatory responses, further compromising the integrity of the skin barrier [36,37].

OXIDATIVE STRESS AND FREE RADICAL GENERATION: UVA and UVB stimulate the production of reactive oxygen species within the skin, leading to oxidative stress. Excessive reactive oxygen species can oxidize lipids, proteins, and DNA in the skin, disrupting the structure and function of the skin barrier [36,38]. For instance, this occurs through the oxidation of lipid components such as squalene, increased free fatty acids, and inflammatory factors, enhancing skin keratinization and inflammation [39,40].

INFLAMMATORY RESPONSE: UV radiation induces acute and chronic inflammatory responses in the skin. UVB exposure often leads to acute inflammation, such as sunburn, due to the release of cytokines and the infiltration of white blood cells. Prolonged UV exposure can result in chronic inflammation. For example, sustained activation of the NF-κB and p38 MAPK pathways leads to the secretion of IL-1β, IL-1α, IL-6, and TNF-α, as well as to the development of the senescence-associated secretory phenotype [41], all of which contribute to ongoing damage to the skin barrier [42,43].

IMMUNOSUPPRESSION: UV radiation-induced immunosuppression is well documented and significantly reduces the antigen-presenting capabilities of Langerhans cells and dermal dendritic cells in humans [43]. Additionally, research by Weber et al [44] found that UV exposure can directly suppress T cell activation – independent of antigen-presenting cells – by excessively activating the p38 and JNK pathways. This activation blocks T cell receptor (TCR)-mediated phosphorylation of ERK and IκB. Consequently, transcription factors such as c-Jun, c-Fos, Egr-1, and NF-κB are downregulated, leading to decreased cytokine production, including IL-2, IL-4, IFN-γ, and TNF-α, following TCR stimulation. UV exposure also inhibits pre-activated T cells, indicating that UV radiation impairs the activation and function of T cells.

AGING: Recent studies suggest that aging leads to the stiffening of the extracellular matrix in the dermis, altering the mechanical microenvironment. This change promotes epidermal stem cell differentiation and increases the fragility of hemidesmosomes, resulting in the loss of epidermal stem cells [45]. Consequently, this impairs the repair and regeneration of the epidermis, adversely affecting the skin barrier.

NUTRITION:

This category encompasses some of the most extensively studied factors within the acne exposome, including dairy and high-sugar/high-fat diets. High intake of dairy and sugary foods can promote the secretion of insulin and insulin-like growth factor 1 (IGF-1). Elevated levels of insulin and IGF-1 increase androgen receptor activity, leading to enhanced sebum production. Additionally, free IGF-1 can stimulate excessive proliferation of keratinocytes [25,46]. A large-scale epidemiological study has demonstrated that individuals with obesity exhibit higher TEWL values [47], which may be linked to adipokines and leptin [48]. Moreover, diet and obesity can influence the skin microbiome [26].

IATROGENIC DAMAGE:

Patients with acne vulgaris who have been treated with benzoyl peroxide often show increased sebum levels, stratum corneum hydration, and TEWL values, alongside decreased microbial diversity [49]. This evidence suggests that benzoyl peroxide use can damage the skin barrier and disrupt the skin’s microecology. Tretinoin, another common treatment, suppresses sebum production and accelerates epidermal turnover, resulting in thinner skin, dryness, and flaking – manifestations of barrier damage. Additionally, procedures such as chemical peels and phototherapy can temporarily damage the skin barrier through mechanical, photochemical, or photothermal effects, and if not properly managed, can lead to secondary skin damage.

INAPPROPRIATE SKIN CARE:

Excessive cleansing and the use of alkaline cleaning products are recognized risk factors for acne and skin sensitivity [50,51]. Surfactants in cleansers can directly damage the skin barrier and alter the skin’s pH, which affects desmoglein proteins and enzymes involved in skin barrier repair and disrupts the skin microbiome [52]. Some patients fail to select skincare products appropriate for their skin type, use products with an excessive content of toxic substances, or use banned drugs such as hormones, which can directly damage the skin or activate oxidative stress and inflammatory responses, thus breaking down the skin barrier [53,54].

AIR POLLUTION:

Mixtures of particles, chemicals, and gases released from natural and anthropogenic sources can harm the skin barrier through oxidative stress and inflammation [55]. A prospective cohort study revealed that exposure to environmental pollutants affects sebum levels and composition, which is detrimental to the stability of the stratum corneum [56]. Certain air pollutants can penetrate the stratum corneum, triggering lipid peroxidation and stimulating the release of pro-inflammatory mediators via the Nrf2 or NF-κB pathways [55]. Particulate matter can upregulate the TLR/NF-κB pathway to amplify inflammation [40], and exposure to particulate matter 2.5 in human keratinocytes has been shown to increase levels of cyclooxygenase-2 and prostaglandin E2, leading to the downregulation of filaggrin expression [57]. This disrupts the skin barrier and creates a vicious cycle.

CLIMATE:

Epidemiological studies have identified temperature and humidity changes as triggers for sensitive skin [58]. Temperatures above 43°C can directly activate specific members of the transient receptor potential (TRP) superfamily, particularly TRP vanilloid 1 (TRPV1) [59], which is responsible for sensing heat and pain. TRPV1 is a non-selective ion channel receptor widely expressed in skin tissues, including keratinocytes, peripheral sensory nerve fibers, and immune cells. It can be activated by various exogenous or endogenous inflammatory mediators, triggering the release of neuropeptides and neurogenic inflammation [60], thereby compromising the skin barrier. Inflammatory mediators can also significantly lower the activation threshold of TRPV1 [61]. A large observational study in China indicated that low humidity is more likely to trigger sensitive skin [62], possibly due to damage to the skin barrier associated with changes in TEWL and sebum levels.

PSYCHOLOGICAL FACTORS:

Corticotropin-releasing hormone plays a crucial role in the body’s response to stress, with its system molecules highly expressed in the skin of patients with acne vulgaris, particularly in the sebaceous glands. These molecules can participate in inducing inflammation and activating immune responses [63]. Sleep disorders can lead to imbalances in facial sebum secretion and increased oxidative stress, further triggering inflammatory responses. These changes can disrupt skin homeostasis and inflammatory pathways, ultimately leading to dysfunction of the skin barrier [64,65].

Repairing the Skin Barrier in Acne Vulgaris

ACTIVE AND STANDARDIZED TREATMENT OF THE PRIMARY DISEASE:

Increased sebum production, abnormal lipid composition, excessive keratinization, microbial dysbiosis, and inflammatory responses in patients with acne vulgaris can all contribute to skin barrier damage. Therefore, the initial step in repairing the skin barrier in these patients is to standardize the treatment of the underlying disease. This includes strengthening health education to enhance patients’ understanding of their condition and encouraging the active avoidance of factors that can further compromise the skin barrier.

COSMECEUTICALS:

Numerous studies have shown that cosmeceuticals can effectively repair the skin barrier by influencing keratinocyte formation, improving stratum corneum function, modulating intercellular lipids, suppressing inflammatory factors, and restoring the skin microbiota. For example, ceramides can replenish natural lipid components and stabilize the skin barrier structure [66]. Plant extracts, such as paeoniflorin and madecassoside, offer anti-inflammatory and reparative effects [67]. Additionally, probiotics and prebiotics can maintain and restore the skin microbiome, thereby enhancing the skin barrier [68]. The adjunctive treatment of skin diseases with cosmeceuticals has become widely popular in China, achieving positive therapeutic effects.

LOW-LEVEL LASER THERAPY:

Lasers, light-emitting diodes (LEDs), and other light sources, through non-thermal effects, regulate cellular activity, a process known as photobiomodulation [69]. This approach can promote the synthesis of cellular ATP, stimulate keratinocyte proliferation, inhibit the release of inflammatory cytokines, such as IL-6, IL-1, and TNF-α, and improve overall skin barrier function. Clinically, red light, yellow light, and large-spot low-energy Q-switched 1064-nm lasers are commonly used for these purposes.

MESOTHERAPY:

Mesotherapy [70,71] is an emerging technology in the field of aesthetic dermatology and represents a significant advancement in transdermal drug delivery. The potential mechanisms by which mesotherapy enhances the skin barrier include mechanical stimulation from microneedles, which initiates the skin’s repair processes; the release of platelets and growth factors due to localized minor bleeding during microneedle treatment; and the direct delivery of skin-structuring and anti-inflammatory components deep into the skin.

Conclusions

Patients with acne vulgaris have compromised skin barriers, not only due to the patient’s own sebum, keratinocytes, microbial abnormalities, and inflammation but also due to various exposome factors that damage the skin barrier, forming a vicious cycle. Repairing the skin barrier is crucial for improving the efficacy of acne vulgaris treatment, preventing recurrence, and reducing secondary skin sensitivity. Various barrier repair methods, including cosmeceuticals and photobiomodulation, have shown positive results. However, since barrier damage extends beyond the stratum corneum, developing technologies that can penetrate and deeply repair the skin is essential. Mesotherapy shows potential as a breakthrough approach, but issues regarding its efficacy, patient compliance, and the safety of injection components require further research. Continued exploration of acne vulgaris pathogenesis and skin barrier impairment will lead to more effective treatments, ultimately benefiting patients.