Why Have A Skin Barrier?
Let us go back many eons in time and imagine that first fish that first attempted to venture out onto land. How could it retain its body water (for most cells are about 80% water), if it left its wet world and were to live on land? How could it keep the water in its cells from evaporating away into the dry air? This new world was a hostile one that threatened to turn our fish explorer from a plum into a prune? This newcomer to land needed some type of ‘permeability barrier’; it needed some form of waterproofing. Biologists call the outer protective covering of plants and animals, their ‘integument’; we call ours ‘skin’.
In mammals, including man, the barrier to loss of body water is provided by the outermost layer of skin, the ‘stratum corneum’. This tissue is made up of multiple stacks of flattened cells or ‘corneocytes’, each of which is encased in a thick coating of fat (or ‘lipid‘). The stratum corneum can be likened to a brick wall. The cells of the stratum corneum no longer possess nuclei or any other organelles like mitochondria; they are by all accounts ‘dead’. These ghost cells are the bricks in our brick wall model; and the fatty matrix that surrounds them is the mortar. This wall – the layers upon layers of corneocytes with their surrounding lipids – provides a formidable barrier to the outflow of water from our interiors. It also produces a protective shield against the entry of noxious materials, such as bacteria or allergens, from the surrounding environment.
But don’t take the bricks-and-mortar image too literally, because the mortar of the stratum corneum is not amorphous like cement or a pat of butter. The fats or lipids of the mortar have an orderly configuration. They are arranged into pairs of sheets, or ‘lamellar membranes’. And multiple layers of these membrane structures fill the spaces between the corneocytes. The cells are held tightly to one another by specialized protein bridges, the ‘corneodesmosomes’
This in a nutshell is the skin’s barrier. This barrier accomplishes a whole set of critical defensive functions that extend beyond holding body water in and keeping microbes and foreign molecules out. For example, the stratum corneum also blocks the penetration of ultraviolet light, filtering much of it out before it even reaches deeper into the skin, where most of the pigment or ‘melanin granules’ reside. Melanin is in fact the second line of defense against the penetration of ultraviolet rays. The stratum corneum is the vanguard of that action.
How the Skin Barrier Works
Simply stated, the bricks – that is those flattened cells called corneocytes – provide a substantial defense against physical trauma, against the ordinary frictional wear and tear of life. Tough protein polymers, called ‘keratins’, that fill the corneocyte interior give the skin much of its remarkable mechanical strength. The bricks are also needed to provide a stable scaffold for the lipids (the lamellar membranes) in the mortar. This duty is revealed in some types of inherited skin disorders called ichthyosis in which a genetic defect impairs the formation of the outer surface of the corneocytes. When the wall of the corneocyte – its ‘cornified envelope’ – is malformed, the lamellar membranes are disorganized and as a result, the barrier to water loss is impaired.
Thus, the corneocytes literally play a supporting role in the functioning of the permeability barrier. The lipids in the lamellar membrane structures are the principal players; they are the workhorses of the barrier. These lipids are unusually water-resistant or ‘hydrophobic’. They are a mixture composed of ceramides, cholesterol, and free fatty acids. One particularly critical species is linoleic acid, which is considered an essential fatty acid because it cannot be made in the body, but must be acquired through the diet, just like most vitamins. The lipids that coat the cells of the stratum corneum are so water-repellant, that not only do they hold our body water inside, but they also allow us to loll for hours in bathtubs or to swim at will, without drowning though our skin.
Still other ingredients in the mortar combat infections. These include both the free fatty acids and several proteins that fight infection, called ‘antimicrobial peptides’. This remarkable tissue, the stratum corneum, with its the bricks and mortar arrangement, and the underlying epidermis, which produces and keeps the stratum corneum operational, provide many of the defensive functions of the skin, including the one most critical for life on land, the permeability barrier.
When and How Things Can Go Wrong
Inherited abnormalities of either the bricks or mortar can compromise barrier function, leading to a wide range of diseases, such as ichthyosis, eczema or atopic dermatitis, and psoriasis. Likewise, the barrier can be damaged by exposure to solvents, detergents, or the ultraviolet B rays in sunlight. Sometimes both inherited abnormalities and acquired stressors of barrier structures can converge to further compromise barrier function. Atopic dermatitis, the most common cause of eczema in children, is a prime example of this sort of collusion. An inherited defect in the protein filaggrin is present in most people with atopic dermatitis, yet they usually do not have a rash or outbreak of eczema all of the time. It takes a “second hit” – a harsh soap, or a skin infection, or encounters with an allergen – to further damage the barrier and provoke the dermatitis.
How Does a Defective Barrier Lead To Inflamed Skin?
Because permeability barrier function is so critical for life in a terrestrial environment, the underlying cells of the epidermis are attuned to the competence of the barrier. Skin deploys multiple types of sensors, which, can signal the underlying epidermis when the barrier is failing to repair the defect and restore normal function. One family of signaling molecules, the ‘cytokines’ and growth factors, induce the underlying epidermis to produce more cells and more lipid, which together will reconstitute the bricks and mortar. But here’s the hitch: if the barrier abnormality persists, as it does in inherited disorders, like ichthyosis or atopic dermatitis, and perhaps even psoriasis, then the cytokines eventually make their way down to deeper layers, where they recruit an inflammatory response. The infiltrate can include inflammatory cells, such as the Th2 lymphocytes and eosinophils in atopic dermatitis, that can in turn aggravate the barrier abnormality, and create a vicious cycle. We have termed this scheme the ‘ouside-inside’ and then ‘back to outside’ pathogenesis of inflammatory skin diseases.
The Outside-to Inside and Back to Outside Pathogenesis of Atopic Dermatitis:
An inherited defect in filaggrin can render the barrier vulnerable. The addition of an external stressor, such as low humidity or colonization with pathogenic strains of Staphylococcus, further challenges the skin’s barrier and the outward leakage of water increases. This leakage causes signalling molecules, called cytokines, to be released that attract inflammatory cells including Th-2 lymphocytes, into the skin. The weakened barrier also allows the ingress of allergens coming in contact with the skin. These allergens further prime the immune system to respond with the recruitment of Th-2 cells. These lymphocytes in turn release other signalling molecules, some of which further damage the skin barrier, and in so doing provoke the release of additional pro-inflammatory cytokines. The even more leaky barrier allows the ingress of more allergens, which provoke more inflammation, and further weaken the barrier. A vicious cycle is now underway. Nonetheless, the inflammation that ensued is a direct consequence of the barrier defect. Therefore, once the barrier is restored by the epidermis or by appropriate treatment with barrier repair medications, the inflammation will resolve.