Role of NHE1 for skin acidity and barrier function

( Eung Ho Choi ),( Hyun Kang ) 한국피부장벽학회 2023 한국피부장벽학회지 Vol.25 No.2

The skin barrier consists of the stratum corneum (SC) and tight junctions, with skin surface pH, typically ranging from 4.5 to 5.5, playing a critical role in various aspects of robust skin barrier function. Skin barrier function relies on a delicate balance of SC intercellular lipids, natural moisturizing factors (NMFs), and acidity. Disruptions in any of these components can lead to barrier dysfunction, resulting in dryness, irritation, and various skin ailments. Increased skin pH and basal transepidermal water loss (TEWL), compromised SC integrity, reduced skin hydration, and elevated serine protease (SP) activity are all correlated with shifts in skin acidity. Skin pH is influenced by both intrinsic and extrinsic factors. Preserving mildly acidic pH at the skin surface is imperative for a healthy skin barrier. Elevated SC pH is linked with various skin conditions, including neonatal skin, aged skin, and inflammatory skin conditions like atopic dermatitis (AD). AD exhibits elevated skin surface pH, especially in the early stages, correlating with disease severity. Maintaining an acidic environment, such as bathing in acidic hot spring water or using acidic topical treatments, can alleviate symptoms in AD patients and reduce Staphylococcus aureus levels. Initial research on the role of sodium-proton exchanger 1 (NHE1) in skin barrier function found that depleting or inhibiting the NHE1 gene elevates SC pH, impeding lipid processing and skin barrier recovery. The study also examined neonatal skin, uncovering a gradual shift from a near-neutral pH at birth to an adult-like acidic state over several months, attributed to NHE1 activation and the involvement of enzymes such as secretory phospholipase A2. Elevated pH during a specific neonatal period delays skin barrier recovery due to the activation of enzymes like SP. Aged skin is often susceptible to inflammatory skin conditions, dryness, and eczema, which can be exacerbated by impaired epidermal barrier homeostasis. Recent research has revealed that in moderately aged skin, the main culprit for barrier issues is a deficiency in SC acidity due to reduced expression of the NHE1. Additionally, in moderately aged skin, decreased NHE1 levels lead to elevated SC pH, resulting in defective lipid processing and delayed formation of lipid membranes. These abnormalities can be rectified by acidifying the SC, forming the basis for acidification therapies widely used to treat pathological dryness and eczema in moderately aged individuals.

The Effect of Airborne Particulate Matter on Skin Barrier Function in Seoul Analysed As Real World Data

( Sunyoung Cho ),( Nayoung Kim ),( Wonjin Seo ),( Taeryoung Lee ),( Sekyoo Jeong ),( Hyunjung Kim ) 한국피부장벽학회 2018 한국피부장벽학회지 Vol.20 No.2

The skin is the outermost barrier that directly and continuously contacts environment. In order to develop preventive strategies against skin damage, inflammation, and skin aging by the airborne particulate matter (PM) in Seoul Metropolitan area, we have been investigating the deleterious effects of PM on skin barrier, and its underlying mechanisms. Previous studies reported that PM can penetrate the barrier-damaged skin area and induce inflammatory responses in keratinocytes. Once reaching the dermal layer, PM can also inhibit collagen synthesis in dermal fibroblast. However, there are few reports about the direct effects of PM on skin barrier function. In this study, using a newly developed IoT-based at-home device measuring trans-epidermal water loss (TEWL) and stratum corneum hydration (SCH), we investigated the potential correlation between PM and skin barrier function in daily based measurements. Total 26 participants (13 healthy volunteers and 13 atopic dermatitis-diagnosed volunteers) were enrolled for the study and participants were administrated to measure the TEWL and SCH at least once a day for 5 months. During the same period, daily PM concentration, UV irradiation strength, ambient temperature and relative humidity data were also collected and analysed against participants-generated clinical data. As results, while skin barrier function, expressed by TEWL, in healthy volunteers was not affected by PM, impairment of skin barrier by PM was observed in atopic dermatitis patients. These results suggest that PM can aggravate skin barrier function in predisposed skin, such as atopic dermatitis. Since TEWL data can also provide the information about the basal skin barrier condition, daily based TEWL measurement can be used for not only identifying more susceptible groups for PM induced skin damages, but also evaluating the efficacy of various preventive strategies, including cosmetics.

Skin Barrier in Aged Skin

최응호 ( Eung Ho Choi ),( Hwa Young Park ) 한국피부장벽학회 2010 한국피부장벽학회지 Vol.12 No.1

Epidermal permeability barrier function is normal in aged skin under basal conditions. However, aged skin barrier is disrupted more easily and repaired more slowly compared to young skin, which originate from an overall deficiency in all key epidermal lipids (especially cholesterol), a decrease of stratum corneum (SC) intercellular lamellae and diminished lamellar body secretion. Therefore aged skin is easily afflicted by inflammatory skin diseases, dry skin and eczema which could be triggered or exacerbated by impaired barrier homeostasis. In advanced age (i.e., >75 years in human or >18-24 months in mice), a reduced epidermal lipid synthesis is the main cause of delayed barrier recovery. In contrast the defects of epidermal permeability barrier in moderately aged humans (50-80 years) or mice (12-15 months) are linked instead to defective SC acidity. In moderately aged skin, the abnormal epidermal acidification, in turn, is linked to decreased Na+/ H+ antiporter (NHE1) expression, which lead to increased SC pH. It results in defective SC lipid processing and then delayed maturation of SC lamellar membranes due to suboptimal activation of the pH-sensitive lipid processing enzyme, β-glucocerebrosidase. On the contrary, impaired SC integrity in moderately aged skin is due to increased pH-dependent activation of serine proteases, which leads to premature degradation of corneodesmosomes. In aged skin, basal epidermal calcium gradient is disturbed, which might result from a decrease of TRPV6. Diabetic skin has very similar barrier state to aged skin. Considering the defective epidermal lipid synthesis in advanced aged skin, moisturizer with appropriate lipid content would be beneficial in advanced aged skin. Application of the physiologic lipid mixture containing cholesterol, ceramides and free fatty acids, or a cholesterol-dominant mixture accelerates barrier recovery in advanced aged epidermis. For moderately aged skin, an exogenous acidification of the SC could be suggested. And some therapeutic implications are suggested for impaired epidermal calcium gradient in aged skin.

Psoriasis and Skin Barrier

( Si-hyung Lee ) 한국피부장벽학회 2017 한국피부장벽학회지 Vol.19 No.1

Skin barrier is crucial for maintenance of healthy skin by preventing the loss of water as well as preventing entrance of pathogenic microorganisms or irritant. Since proliferation of keratinocytes is induced by disruption of skin barrier, impaired barrier function has been suggested to involve the development of proliferative skin disease, including psoriasis, which is well known disease expressing T helper 17 cell-related inflammation. Interestingly, skin barrier-related molecules, including filaggrin, loricrin and ceramide, are down-regulated in lesional skin of psoriasis. Moreover, water-holding capacity and barrier recovery are also impaired in psoriatic lesion. Mice expressing activated STAT3 at keratinocytes showed disrupted barrier function as well as psoriasis-like skin inflammation. Recent studies demonstrated that defects in various skin barrier-related genes, including late cornified envelop proteins, were associated with a risk of psoriasis. In conclusion, skin barrier impairment might have close relationship with psoriasis. However, further studies are required to determine whether impaired skin barrier plays causative role or not in the development of psoriasis.

Inflammaging and Barrier Function in Aged Skin

( Eung Ho Choi ),( Sung Ha Lim ),( Beom Jun Kim ),( Hyun Jee Hwang ) 한국피부장벽학회 2021 한국피부장벽학회지 Vol.23 No.2

Inflammaging is a chronic low-level inflammation associated with aging and drive many age-associated diseases including atherosclerosis, type 2 diabetes, and Alzheimer’s disease. In inflammaging, increased levels of circulating proinflammatory cytokines such as IL-6, IL-8 and TNF-α are observed. In addition, glucocorticosteroid hormone (GC), which has anti-inflammatory effects, is increased in the blood, skin, and mucosa of aging humans and mice. The expression of 11β-hydroxysteroid dehydrogenase type 1 (HSD1), which converts inactive GC to active GC, increases with aging and contributes to the phenotypes of aged skin. In aging skin, barrier function is impaired by various factors. GC activated by 11β-HSD1 may further deteriorate the skin barrier function in aged skin. Stratum corneum lipid levels were decreased in aged skin, however this could be rescued by treatment with an 11β-HSD1 inhibitor. The three main mechanisms responsible for skin pH are disturbed with age. Among them, abnormal function of sodium-hydrogen exchanger 1 (NHE1) is a specific underlying defect in the pH increase in aging skin. Repair strategies for the aging skin barrier are physiological lipid mixtures, NHE1 activators, and acidic moisturizers. Inflammaging and barrier dysfunction are observed in the aged or diabetic skin. The long-standing hyperglycemia observed in type 2 diabetes accelerate the skin aging process, damaging the skin barrier. In aging skin, impaired barrier function increases the cutaneous pro-inflammatory cytokines, both of which are restored by moisturizers. Conversely, inflammaging exacerbates barrier dysfunction. In summary, skin barrier impairment in the aged may lead to skin inflammation, which in turn may lead to systemic inflammation by increasing blood cytokines. Therefore, inflammaging and its sequelae may be prevented or mitigated with barrier repair strategies.

The role of sodium proton exchanger 1 (NHE1) in maintaining normal skin acidity and barrier function

( Eung Ho Choi ),( Hyun Kang ) 한국피부장벽학회 2023 한국피부장벽학회지 Vol.25 No.2

The skin barrier's integrity relies on maintaining a mildly acidic pH on the skin surface, typically ranging from 4.5 to 5.5. This acidity is crucial for various aspects of skin barrier function, including the stratum corneum (SC) and tight junctions. Imbalances in SC lipids, natural moisturizing factors (NMFs), and acidity can lead to skin barrier dysfunction, causing dryness, irritation, and various skin issues. Conditions like neonatal skin, aged skin, and atopic dermatitis (AD) are associated with elevated skin pH, indicating the importance of maintaining an acidic environment. Research highlights the role of sodium hydrogen exchanger 1 (NHE1) in skin barrier function. Inhibiting NHE1 or depleting its gene results in increased SC pH, hindering lipid processing and barrier recovery. Neonatal skin undergoes a transition from a near-neutral pH at birth to an acidic state due to the activation of NHE1 and the involvement of enzymes such as secretory phospholipase A2. Elevated pH during a specific neonatal period can delay the process of barrier recovery. Moderately aged skin often experiences barrier issues, inflammation, dryness, and eczema. Reduced NHE1 expression in moderately aged skin leads to decreased SC acidity, resulting in impaired lipid processing and delayed lipid membrane formation. Acidification therapies, which rectify these abnormalities by acidifying the SC, are commonly used to treat pathological dryness and eczema in moderately aged individuals. In summary, maintaining an acidic skin surface pH is essential for a healthy skin barrier. NHE1 plays a crucial role in regulating this acidity, and disruptions in its function can lead to various skin issues, making it a potential target for therapeutic interventions in skin conditions associated with pH imbalances.

Inflammaging and Barrier Function in Aged Skin

( Eung Ho Choi ),( Sung Ha Lim ) 한국피부장벽학회 2021 한국피부장벽학회지 Vol.23 No.2

Inflammaging is a chronic low-level inflammation associated with aging and drives many age-associated diseases including atherosclerosis, type 2 diabetes, and Alzheimer’s disease. In inflammaging, increased levels of circulating proinflammatory cytokines such as IL-6, IL-8, and TNF-α are observed. In addition, glucocorticosteroid hormone (GC), which has anti-inflammatory effects, is increased in the blood, skin, and mucosa of aging humans and mice. The expression of 11β-hydroxysteroid dehydrogenase type 1 (HSD1), which converts inactive GC to active GC, increases with aging and contributes to the phenotypes of aged skin. In aging skin, barrier function is impaired by various factors. GC activated by 11β-HSD1 may further deteriorate the skin barrier function in aged skin. Stratum corneum lipid levels were decreased in aged skin, however, this could be rescued by treatment with an 11β-HSD1 inhibitor. The three main mechanisms responsible for skin pH are disturbed with age. Among them, the abnormal function of sodium-hydrogen exchanger 1 (NHE1) is a specific underlying defect in the pH increase in aging skin. Repair strategies for the aging skin barrier are physiological lipid mixtures, NHE1 activators, and acidic moisturizers. Inflammaging and barrier dysfunction are observed in the aged or diabetic skin. The long-standing hyperglycemia observed in type 2 diabetes accelerates the skin aging process, damaging the skin barrier. In aging skin, impaired barrier function increases the cutaneous pro-inflammatory cytokines, both of which are restored by moisturizers. Conversely, inflammaging exacerbates barrier dysfunction. In summary, skin barrier impairment in the aged may lead to skin inflammation, which in turn may lead to systemic inflammation by increasing blood cytokines. Therefore, inflammaging and its sequelae may be prevented or mitigated with barrier repair strategies.

Impaired Skin Barrier Due to Sebaceous Gland Atrophy in the Latent Stage of Radiation-Induced Skin Injury: Application of Non-Invasive Diagnostic Methods

Jang, Hyosun,Myung, Hyunwook,Lee, Janet,Myung, Jae Kyung,Jang, Won-Suk,Lee, Sun-Joo,Bae, Chang-Hwan,Kim, Hyewon,Park, Sunhoo,Shim, Sehwan MDPI AG 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.1

<P>Radiation-induced skin injury can take the form of serious cutaneous damage and have specific characteristics. Asymptomatic periods are classified as the latent stage. The skin barrier plays a critical role in the modulation of skin permeability and hydration and protects the body against a harsh external environment. However, an analysis on skin barrier dysfunction against radiation exposure in the latent stage has not been conducted. Thus, we investigated whether the skin barrier is impaired by irradiation in the latent stage and aimed to identify the molecules involved in skin barrier dysfunction. We analyzed skin barrier function and its components in SKH1 mice that received 20 and 40 Gy local irradiation. Increased transepidermal water loss and skin pH were observed in the latent stage of the irradiated skin. Skin barrier components, such as structural proteins and lipid synthesis enzymes in keratinocyte, increased in the irradiated group. Interestingly, we noted sebaceous gland atrophy and increased serine protease and inflammatory cytokines in the irradiated skin during the latent period. This finding indicates that the main factor of skin barrier dysfunction in the latent stage of radiation-induced skin injury is sebaceous gland deficiency, which could be an intervention target for skin barrier impairment.</P>

Urban particulate matter in air pollution penetrates into the barrier-disrupted skin and produces ROS-dependent cutaneous inflammatory response <i>in vivo</i>

Jin, Seon-Pil,Li, Zhenyu,Choi, Eun Kyung,Lee, Serah,Kim, Yoen Kyung,Seo, Eun Young,Chung, Jin Ho,Cho, Soyun Elsevier 2018 Journal of dermatological science Vol.91 No.2

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Particulate matter (PM) is an integral part of air pollution, which is a mixture of particles suspended in the air. Recently, it has been reported that PM is associated with increased risks of skin diseases, especially atopic dermatitis in children. However, it is unclear if PM directly goes into the skin and what mechanisms are involved in response to PM.</P> <P><B>Objective</B></P> <P>To see whether PM could penetrate into the barrier-disrupted skin, produce reactive oxygen species (ROS), and elicit an inflammatory response.</P> <P><B>Methods</B></P> <P>We collected PMs during a winter in Seoul and used cultured keratinocytes for <I>in vitro</I> study and tape-stripped BALB/c mice for <I>in vivo</I> study.</P> <P><B>Results</B></P> <P>Keratinocyte cytotoxicity increased in a dose-dependent manner by PM treatment. IL-8 and MMP-1 mRNA expression and protein levels were significantly increased compared to control by qPCR and ELISA, respectively. Cellular ROS production was increased by PM treatment, and antioxidant N-acetyl cysteine pretreatment prevented induction of inflammatory cytokines IL-8 and MMP-1. In PM-treated keratinocytes, electron-dense subcellular particles were observed by transmission electron microscopy. PM was observed inside hair follicles in both intact and barrier-disrupted skin <I>in vivo</I>. Additionally, intercellular penetration of PM was seen in the barrier-disrupted skin. Repeated PM application induced epidermal thickening and dermal inflammation with neutrophil infiltration. Finally, N-acetyl cysteine could ameliorate skin inflammation induced by PM application.</P> <P><B>Conclusion</B></P> <P>PM penetrates into the barrier-disrupted skin, causing inflammation, demonstrating detrimental effects in the skin.</P> <P><B>Highlights</B></P> <P> <UL> <LI> It is unclear if particulate matter (PM) directly goes into the skin. </LI> <LI> We provide visual images of PM penetrating into epidermis in the barrier-disrupted skin. </LI> <LI> Repeated PM application leads to cutaneous inflammation via ROS-dependent manner. </LI> <LI> It may have clinical implications especially for patients with deficient skin barrier including atopic dermatitis, diabetics. </LI> </UL> </P>

Importance of Stratum Corneum Acidification to Restore Skin Barrier Function in Eczematous Diseases

최응호,강현 대한피부과학회 2024 Annals of Dermatology Vol.36 No.1

Skin barrier function relies on three essential components: stratum corneum (SC) lipids, natural moisturizing factors (NMFs), and the acidic pH of the SC surface. Three endogenous pathways contribute to acidity: free fatty acids from phospholipids, trans-urocanic acid from filaggrin (FLG), and the sodium-proton antiporter (NHE1) activity. An acidic SC environment boosts the activity of enzymes to produce ceramides, which are vital for skin health. Conversely, an elevated pH can lead to increased skin infections, reduced lipid-processing enzyme activity, impaired permeability barrier recover y, and compromised integrity and cohesion of the SC due to increased serine protease (SP) activity. Elevated SC pH is obser ved in neonatal, aged, and inflamed skin. In atopic dermatitis (AD), it results from decreased NMF due to reduced FLG degradation, decreased fatty acids from reduced lamellar body secretion, and reduced lactic acid due to decreased sweating. Moreover, the imbalance between SP and SP inhibitors disrupts barrier homeostasis. However, acidif ying the SC can help restore balance and reduce SP activity. Acidic water bathing has been found to be safe and effective for AD. In three different AD murine models, SC acidification prevented the progression of AD to respirator y allergies. In aging skin, a decrease in NHE1 leads to an increased skin pH. Mild acidic skin care products or moisturizers containing NHE1 activators can normalize skin pH and improve barrier function. In conclusion, maintaining the acidity of the SC is crucial for healthy skin barrier function, leading to significant benefits for various skin conditions, such as AD and aging-related skin issues.