This blog picks up from our first in-depth discussion on Skin Structure & Function to address Stratum Corneum’s major feature of Barrier Defence. Healthy, viable skin does a great job at mounting a barrier between the outside world and our viscera (inner organs). Breakthroughs in Corneobiology show that S. Corneum mounts barrier defences on many fronts, namely as a: 1. Permeability Barrier; 2. Antimicrobial Barrier; 3. Antioxidant Barrier; 4. Immunity Barrier; and 5. Photoprotection Barrier.[1,2]
Skin’s Barrier Fronts are under constant assult from Exogenous Factors like UV Rays (UVR), air pollutants, harsh chemicals, harmful microbes and allergens. Stratum Corneum’s Barrier Defence Systems are usually capable of neutralizing or at least mitigating these outside threats, provided that the individual is sufficiently healthy. Barrier Defence can also be weakened due to Endogenous Factors, most commonly Hereditary Disorders or Mutagenesis (gene mutations). The emergence of multifactorial Skin Disease States (Dermatoses) like Atopic Dermatitis (eczema), Rosacea, Psoriasis, Acne Vulgaris and others, arise from the interplay between these Exogenous & Endogenous Factors. In skin clinics, these complex and broad-spectrum dermatoses are usually managed and sometimes treated with topical and oral interventions—(corticosteroids, benzoyl peroxide, retinoids, cholesterol lowering “statins”)— that keep symptoms at bay, but do little at repairing Skin Barrier Defences. In fact, novel research in Dermatology have shown that strong pharmaceutical approaches actually weaken Skin’s Barrier Defence Fronts (Iatrogenesis). [2]
Skin’s Structural aspect also plays defence roles that work in tandem with some of the Barrier Fronts—(permeability, antimicrobial, antioxidant, immune, photoprotection)— which are: Acid Mantle & Microbiome; Corneocytes; and Multilamellar Lipids. These structural aspects team up with some of the Barrier Defence Fronts to keep us protected and healthy. For now, let’s talk some more about the five (5) Barrier Defence Fronts.
Permeability Barrier
The Permeability Barrier is mainly attributed to skin’s outermost layer, Stratum Corneum. Underlying epidermal layers also contribute to skin’s permeability feature—hence the alternative barrier name, Epidermal Barrier. However, Corneobiologists prefer giving S. Corneum most credit for this because of its 'brick and mortar' wall pattern. Under light microscopy, Stratum Corneum's appearance is likened to a mason’s wall, with the cells or Corneocytes serving as bricks while Multilamellar Lipids serve as the mortar dispersed between the interstices. Corneobiologists suggest that these Barrier Lipids might be the proverbial keystone of barrier integrity. Multilamellar lipids, often referred to as just Lamellar Lipids, are comprised of a lipid triad of: 1. Ceramides, 2. Cholesterol & 3. Free Fatty Acids, that are important to the maintenance of the Epidermal Barrier. The concept of oil repels water is what these barrier lipids are based on. It is known that most foreign intruders are water-soluble by nature, Hydrophilic, and can easily enter and reside in the body’s water phase. Barrier lipids being Lipophilic in nature (oil-loving) repel most of these water-soluble intruders from entering through available penetration routes (Intracellular Route, Intercellular Route, Follicular Route & Eccrine Route).
Let’s discuss these Barrier Lipids in more depth to really understand how they maintain the integrity of the Permeability Barrier.
Barrier Lipids contributing to Permeability Barrier
Barrier or Multilamellar Lipids, constitute a lipid triad comprising of Cholesterol, Ceramides & Fatty Acids. These lipids are in a delicate ratio of 40%-50% Ceramides : 25% Cholesterol : 10-15% Free Fatty Acids.[2] They orient themselves in a very particular crystalline pattern referred to in Crystallography as Orthorhombic, one of seven other patterned orientations solids can find themselves arranged. An orthorhombic orientation allows for lipids to be closely and orderly packed. The packed lipids further stack themselves into multi-layered sheets called Lipid Lamellae or Multilamellar Lipid Structures, which can be likened to lasagne sheets.
If this well-arranged Lipid Lamellar is disrupted, the crystalline structure collapses (switches phase from solid to liquid) resulting in compromised barrier integrity. Disruption of the crystalline structure is usually because of: 1. a deficiency in polyunsaturated fatty acids (PUFAs); 2. lipid peroxidation (LPO) of PUFAs; 3. irregular lipid packing; or 4. frequent use of alkaline soaps. [3,4] The most notable consequence of this is evaporation of skin moisture into the environment, Trans-Epidermal Water Loss (TEWL), and skin dehydration. Breaching of the skin barrier by opportunistic invaders becomes inevitable. Polyunsaturated Fatty Acids are essential to the well-being of the Multilamellar Lipid Structure and deserve a brief spotlight.
To better appreciate PUFAs we should backup a bit and mention the three (3) major classes of nutrients generally required by our body to carry out everyday chores, these are: 1. Carbohydrates; 2. Proteins; 3. Lipids and are known collectively as Macronutrients or ‘macros’. However, there are some chores that require specially outsourced tools that the body can only obtain from particular foods. This special group is referred to as Polyunsaturated Fatty Acids (PUFAs) and is a subclass of the Lipid family. PUFAs take care of a range of things in our body, from blood clotting to muscle movement, lowering bad cholesterol to postponing heart disease and stroke. As you can see, there is a reason why ‘essential’ is tagged onto these neat fatty acids. Say hello to Omega 6 (Linoleic acid & Arachidonic acid) and Omega 3 (Alpha-linolenic acid [ALA], Eicosapentaenoic acid [EPA] & Docosahexaenoic acid [DHA]). These are mainly found in fish, nuts and seeds— foods that are the hallmark of the Mediterranean Diet. You might have also heard about Omega 9 (oleic acid), well here’s a bit of a twist, Oleic acid is a Monounsaturated Fatty Acid which is important as well but more so in Hair Care Science. The World Congress of Dermatology, which hosts annual symposiums addressing common skin conditions, suggest that Essential Fatty Acid Deficiency (EFAD) specifically affects Barrier Lipids of Stratum Corneum.[5]
The quantity and quality of Ceramides often depends on Omegas 3 and 6.
The skin has intelligent mechanisms in place that help prevent collapse of the lipid lamellae. Such mechanisms are mediated by modulatory complexes called Lipid Phase Modulators, namely Ceramide 1 & 3. Ceramides are sphingolipids that are essential not only as phase modulators but in helping trap and retain moisture. Ceramide 1 often binds with Linoleic acid (Omega 6) to yield a more stable and effective phase modulator known as Ceramide 1 Linoleate. Deficiencies in PUFAs, in this case Omega 6, single-handedly is responsible for the absence of the guardian Ceramide 1 Linoleate, which in turn results in the collapse of the crystalline structure and loss of Permeability Barrier integrity. Scientists have discovered that in Essential Fatty Acid Deficiencies (EFADs), the Ceramide-1 lipid compound senses the urgency of things and frantically grabs on to the nearest fatty acid substitute, most commonly Omega 9 (Oleic acid), complexing with it to form the less than ideal counterpart, Ceramide 1 Oleate— a compound observed at elevated levels in Dry Skin (Xerosis). [3,5,6,7]
Corneocytes contributing to Permeability Barrier
Corneocytes themselves aid in preventing penetration of foreign matter, via cell-to-cell stitching of neighbouring corneocytes (Tight Junctions) as well as by their Cornified Cell Envelopes (CE). We learnt in our first blog that the development of the Cornified Cell Envelope is the keystone of the Corneocyte Compaction Process of the Keratinocyte Life Cycle. Incomplete cellular compaction leave gaps in the brick and mortar structure of S. Corneum. These gaps allow intruders to breach the physical barrier, penetrating further into deeper skin regions to rage havoc (Inflammatory Cascades). Dysregulated desquamation or cell shedding can also compromise the integrity of the Permeability Barrier due to incomplete dissolution of corneodesmosomes. This results in partial cell shedding that leave gapping entrances for pathogens and allergens. This scenario is especially seen in dry, flaky, fish-scale skin (Ichthyosis). The next blog on Common Skin Pathology will dive deeper into these dermatoses or skin diseases.
Recall that Transglutaminase 1 (TG1) initiated the process of replacing a keratinocyte’s plasma membrane with a thickened layer of several crosslinked proteins— (loricrin, cystatin, small proline-rich proteins [SPRs] desmoplakin, involucin, elafin, filaggrin, envoplakin, cornifin, type 2 keratins, and desmoglein)—to form a monomolecular layer of Acylglucosylceramides. We established that this monomolecular layer serves as the scaffold that supports the overlying deposition of multilamellar lipids. Poorly formed CE compromises the deposition of lamellar lipids, which in turn increases susceptibility to foreign matter penetration. An incomplete Cornified Cell Envelope has a knock-off effect on skin surface milieu i.e., Acid Mantle and Microbiota, particularly skin alkalinity (>5.0) as well as imbalances in skin surface microflora (between good & bad microbes) respectively. Interestingly, microbiota ramifications often coincide with increase in Staphylococcus aureus (bad microbe) susceptibility, commonly seen in Impetiginized Eczema. Poor cell envelope formation also triggers the Innate Immune System which in turn activates the Adaptive Immune System, resulting in dysregulated Inflammatory Cascades observed in dermatoses like Rosacea, Atopic Dermatitis, Psoriasis, Ichthyosis, Xerosis etc. Filaggrin deficiency (one of the crosslinked membrane proteins) is usually the prime cause of poor cornified cell envelope formation. (More on skin disease states in our next blog, Common Skin Pathology).
Antimicrobial & Immune Barrier
The very first line of defence against pathogens begins at the Skin Surface Milieu, Skin Microbiome & Acid Mantle (sebum & sweat concoction). Commensal skin microbes (Microflora) can be thought of as the ‘good guys’ since these have permanent residence on the skin’s surface and serve to restrict the growth of bad microbes while supporting Barrier Integrity. Staphylococcus epidermidis is one such ‘good guy’ that secretes Antimicrobial Peptides (AMPs) which keep bad microbes at bay. In addition, S. epidermidis serves as an immunomodulator and promotor of barrier function by producing essential Ceramides necessary to maintain the Lipid Lamellar Crystalline Structure. [8,9]
Corneocytes, being the next in line on the defensive, can detect pathogens and allergens via Pattern Recognition Receptors like TLR2, and can secrete Cytokines (Immunomodulatory Proteins) that recruit other immune players. TLR2 can also induce the formation of cell-to-cell tight junctions at Stratum Granulosum and Stratum Spinosum, preventing further penetration of foreign matter before they reach the dermal-epidermal junction. Pattern Recognition Receptors which are located on corneocyte membranes, are the Immune System’s first responders to invaders, particularly the Innate component. Skin’s Antimicrobial Defences come in three main types: Defensins, Cathelicidins and Dermicidins (cationic AMPs). From the family of defensins, HBD-2 (Human Beta Defensin-2) neutralize gram negative bacteria like Pseudomonas aeruginosa or yeasts like Candida albicans. LL-37 (the active form of Cathelicidin) also can destroy some microbes once enzymatically activated by Serine Endopeptidases like KLK5. Interestingly, scientists have come to realize that these AMPs (HBD-2, HBD-3, Cathelicidin LL-37 & S100A7) all have supportive Epidermal Barrier Functions, specifically by promoting tight junction formation. [8] Corneocyte damage due to poorly developed Cornified Cell Envelopes or Lipid Peroxidation may not be able to solicit early innate responses, thereby increasing vulnerability to intruders.
Resident immune cells of the skin, Langerhans cell, can become activated by allergens or by neighbouring keratinocyte signalling (Cytokines). Langerhans cell found in Stratum Spinosum, secrete cathelicidins from their Birbeck’s granules. Regulation of cathelicidin is very important to thwart any overexcitabilities which might lead to inflammation. Inhibitors of Serine Endopeptidases ensure this delicate regulation; their absence causes the development of pro-inflammatory variations of cathelicidin resulting in dysregulated inflammatory cascades often seen in Rosacea. Langerhans cell are able to sample allergens with their octopus-like limbs (dendrites) by projecting them up in-between cells of the overlying Stratum Granulosum. Full dendritic extension is made possible by the fluid-mosaic membrane health of Langerhans cell. Aging causes shortening of dendrites, and therefore lower availability of sampling limbs at higher epidermal layers (S. Granulosum). This means that pathogens and allergens can advance deeper into the epidermal layers before this immune sentinel can respond. Once a Langerhans cell makes contact with a foreign entity it leaves its post, travels across the dermal-epidermal junction to lymphatic vessels in the dermis and arrives at a Lymph Node. At the lymph node, Langerhans cell seek the assistance of the more specialized Adaptive Immunity, by presenting allergens to T-Cells found in the lymph node (Antigen Presentation). Once Adaptive Immunity recognizes the allergen an immune response is mounted with Antibodies and Killer T-Cells.
As an interesting side note, Langerhans cell give up their posts as tissue resident immune sentinels whenever the epidermis is damaged by burns like sunburn or chemical burns. During this time, skin is even more susceptible to pathogens. Once the environment heals, Langerhans cell return to their posts.
Antioxidant Barrier
Stratum Corneum, being the foremost layer, is in direct contact with the environment and its accompanying Oxidative Stressors like air pollutants, UVR (Photo-Oxidative Stress), pathogen-generated reactive oxygen species (ROS) and chemical oxidants. While these Exogenous factors are the main threat to Barrier Integrity, internal metabolic processes as well as mitochondrial respiration produce Endogenous oxidative by-products. Thanks to the Cutaneous Antioxidant Barrier, skin is equipped with counter oxidative mechanisms that can neutralize harmful Free Radicals. These counter measures are either Enzymatic (Superoxide Dismutase, Catalase, Glutathione Peroxidase, Glutathione Reductase) or Non-enzymatic (Vitamins E & C; hormones Estradiol & Melatonin; Coenzyme Q10; Uric Acid) and work together dynamically. These antioxidant systems are distributed throughout Stratum Corneum on a gradient, with highest concentrations present at deeper S. Corneum levels, i.e S. Compactum. [10]
Melatonin, one of the non-enzymatic antioxidants, has been shown scientifically to promote Longevity and is a hormone produced by our Pineal Gland or “Third Eye”.
Imbalances between these two Free Radical scavenging mechanisms (enzymatic & non-enzymatic) can lead to: 1. DNA damage (nuclear & mitochondrial), 2. Lipid Peroxidation (cell membrane disruption) and 3. Amino Acid denaturation— cumulatively referred to as Biological Aging. [10] In other instances, the Redox Balance may be disrupted due to quenching of endogenous antioxidant systems, as antioxidants find themselves overwhelmed with scavenging Free Radicals. Reactive Oxygen Species (ROS), which is a subset of oxygen-containing free radical compounds, also do damage to DNA, Lipids and Proteins. Here are some common ROS compounds: Hydroxyl, Peroxyl & Alkokyl radicals; Superoxides; Hydrogen Peroxide; Singlet Oxygen; and Organic Peroxides. Vitamin E, also known as Alpha-Tocopherol, tend to have membrane lipid stabilizing effects and sequesters Singlet Oxygen the best. Vitamin C (Ascorbic Acid) works synergistically with Vitamin E as Free Radical Scavengers and has the capacity to regenerate Vitamin E if damaged.
Scientific discoveries in the arena of Longevity promotion hints to the notion that Eustress (beneficial stressors like physical Activity, caloric restrictions or cognitive activity) can in fact promote Adaptive Endogenous Defence Responses, thereby fine tuning the body’s ability to quickly combat threats. Other research has shown that the combined approach of oral and topical associated antioxidants at doses that mimic cutaneous antioxidant concentrations greatly aids the Antioxidant Barrier Defence. [10,11]
Photoprotection Barrier
Lastly, we have the Melanin Barrier also known as the Photoprotection Barrier. This barrier feature directly combats the harmful effects of short and long waves on the Electromagnetic Spectrum. Shorter wave lengths like UV rays (UVR), are most known to have damaging effects on our skin and DNA. Ultraviolet frequencies (UV) make their way from cosmic origins, daring to penetrate earth’s atmosphere and our skin where they generate UV-Induced Free Radicals. There are three major UV rays: UVC, UVB and UVA. The first, UVC (100nm-280nm), is the most damaging ray on the ultraviolet spectrum which mostly gets trapped, thankfully, by the Ozone Layer. UVB (280nm-315nm) is able to penetrate the ozone as well as all of the epidermal layers, down to Stratum Basale. The visible evidence of UVB’s effects on the skin manifest as Sunburns (Solar Erythema). Finally, UVA (315nm-400nm) is able to penetrate the ozone layer, the epidermis, all the way to the Dermis. This ultraviolet long wave is known to cause damage to DNA (UV Mutagenesis) resulting in skin diseases like Melanoma. Beside harmful frequencies like UVR on the electromagnetic spectrum, skin scientists suggest that other light waves, like ones on the Visible Light Spectrum (400nm-700nm), also generate Free Radicals on contact with skin. Thankfully, Stratum Corneum is equipped with Photoprotective features that attenuate these distant rays either by: Scattering (reflection/deflection); Absorption; or through DNA protective mechanisms that shield our genetic information.
Optical Reflection is the physical property of some materials to reflect light waves, Stratum Corneum’s physical structure is capable of this and is dependent on the thickness and cell compaction of this stratum and the rest of the viable epidermis. Attenuation of radiation is largely contributed to Absorption by specialized light-trapping compounds called Chromophores. These compounds have optical absorbances at the level of S. Corneum and the other layers of the epidermis. Urocanic Acid is a popular chromophore that has good overall wavelength absorbance but absorbs optimally around 277nm. Peptide bonds also absorb light waves, with maximal absorbance around 240nm. Melanin, commonly considered the Endogenous Sunscreen, is a pigment produced by Melanocytes and stored in Melanosomes that has broad but variably absorbance between 250nm-1,200nm but works best on shorter waves. [1,12 ] Lastly, DNA protective mechanisms which are made possible by the clustering of Melanosome over a keratinocyte’s nuclear envelope, physically shield DNA from mutagenic radiation. Melanosomes containing melanin get transported along the tentacle-like arms of melanocytes, eventually getting transferred to surrounding keratinocytes. Melanin pigment comes in two variants, Eumelanin and Pheomelanin, with the first variant (eumelanin) being the more imminent player with good free radical scavenging abilities; in contrast to the latter variant (pheomelanin) being more unstable by nature, often spontaneously generating reactive oxygen species that increase skin’s sensitivity to light (Photosensitization) and induce the development of skin diseases like Melanoma. Skin’s Tanning phenomenon (Hyperpigmentation), when induced by intense light rays, is a very noticeable response mechanism that elevates eumelanin concentration through α-MSH-MCR1 pathways. [1]
All in all, Skin’s Barrier Defence features (Permeability Barrier, Antimicrobial Barrier, Antioxidant Barrier, Immunity Barrier & Photoprotection Barrier) come together synergistically to help retain and restore skin health in the most beautiful and elegant way. When skin’s defences are insufficient, well formulated barrier-promoting Skin Care Products are great supplementary aids in complementing skin’s barrier defence mechanisms. In fact, Corneotherapy, the subfield of Dermatology concerned with the repair and retention of skin’s barrier integrity, particularly at the Stratum Corneum level, is pioneering novel approaches that some cosmetic formulators are adopting. Indeed, Corneotherapeutic principles applied to well formulated, Plant-Based Skin Care Products might be by far our best bet to healthy, youthful skin.
Samuel M.T Jones
Bsc. Biological Sciences (Hons.)
PG. Dip. Organic Personal Care/Cosmetic Science
PG. Cert. Barrier Disordered Skin
PG. Cert. Beekeeping
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