Aging is defined as a decline or loss of the ability to adapt to changes over time, causing a progressive deterioration of the integrity of the organism and its functions (1). One of the tissues where the changes associated with the passage of time can be observed more notably. This presents deep modifications when aging, including an increase in generalized inflammation and associated with age. (2).
The skin is the largest organ in the body, and is composed of three layers: epidermis, dermis and hypodermis. However, epidermis and dermis are the most complex, being where most cells reside, while the hypodermis is formed by fat (3). Focusing on the epidermis and dermis, the first refers to the outermost layer, and is in contact with the outside. It forms a waterproof cover, which protects the body against external aggressions and in the face of dehydration (3). Then, the dermis is under the epidermis, and provides structural and functional support to the rest of the skin. The dermis is composed of a wide variety of cell types, including immune cells, blood vessels and lymphatics, neuronal and muscle cells, and provides an interaction network between them (4) (Figure 1).
Figure 1. Scheme of the different layers of the skin. The outermost layer is the epidermis, which generates an waterproof protection layer. Then there is the dermis, which provides support to the rest of the skin. Finally, the hypodermis includes fat.
During aging, the skin undergoes generalized deterioration, and the specific characteristics vary depending on the layer. The aged epidermis has alterations that include the wear of the waterproof barrier of it, thus allowing greater permeability through the skin (5). This causes a greater incidence of skin infections, caused by the entry of pathogenic microorganisms, and greater skin dehydration. Another feature of the epidermis associated with aging is the loss of integrity of the hair follicles, which is an existing structure in the skin that provides a place of growth to the hair (6, 7). This is caused in part by a degeneration of the stem cells of hair follicles. Therefore, there is a decay of integrity into the hair, by the stem cells and their niche, leading to lower hair growth. The inefficient wounds is another of the most described characteristics of aging skin, and includes damage to the epidermis and the dermis (8). In this case, when a wound is generated, an immature tissue is created to replace the damaged. In the epidermis, the cells are not able to divide and mature correctly to generate the outermost layers of the same epidermis, and in the dermis, sufficient factors need to recruit all those involved in said process are not secreted. Thus, both the epidermis and those of the dermis are unable to regenerate the tissue efficiently, increasing the deterioration in the permeability and the general functionality of the skin (8) (Figure 2). In addition, all these alterations are accompanied by an increase in inflammatory signals in the epidermis and dermis cells (2, 9). Even so, despite the fact that many of the skin changes associated with aging have been described, much of the specific alterations that occur, as well as their origin and characteristics, are still unknown.
Figure 2. Summary of some of the skin functions deteriorated during aging. There is an increase in permeability through the skin, a deterioration in the integrity of hair follicles and lower hair growth, as well as an inefficient wound regeneration.
IL-17 is critical of autoimmune and inflammatory chronicles
In a recent study, we have described Interleucin-17 (IL-17) as responsible for generating at least part of the deterioration of the skin associated with aging. Interleucins are part of a group of protein that performs immunintary functions, known as cytokines. In the case of the IL-17, it is a family of cytokines with six members (IL-17A to IL-17F), and the best known and relevant members are IL-17A and IL-17F (10).
As for their specific skin functions, they are related to the elimination of external pathogens, including fungi and bacteria (11). In addition, IL-17A and IL-17F are closely linked to a variety of autoimmune and chronic inflammatory diseases. Autoimmune diseases occur because the immune system of the individual himself attacks their own healthy tissues, by confusing them with external and pathogens, and inflammatory chronicles are characterized by maintaining inflammation features more time than due (10, 11). Inflammation is a mechanism for defense of the body, with repair functions against generated damage. However, this inflammation becomes negative when it lasts over time, facilitating the formation of more added damage and the development of chronic diseases.
An example of autoimmune and inflammatory chronic disease is psoriasis, which affects the skin. In this case, there is a deep modification of the epidermis, where the cells of the epidermis or keratinocytes proliferate excessively, causing structural and functional inflammatory alterations throughout the skin (12). IL-17A and IL-17F cytokines are key in the development of this disease, and there are therapies for these patients in which the activity of both cytokines is blocked (13). With this, it has been shown that patients have an improvement in symptoms and less deterioration in the skin.
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The increase of IL-17 and the aging of the skin go hand in
In this study, we describe both IL-17A and IL-17F cytokines as keys in skin aging. We describe an increase in the expression of IL-17A and IL-17F in the dermis of old mice. Specifically, this increase in expression is only given in some types of immune cells called lymphocytes, which are a main cellular type of the immune system. This increase contributes to the development of age associated with age, which participates in the deterioration of skin functions and integrity.
In this way, and to understand what is the role of IL-17A and IL-17F in the degeneration of aged skin functions, we block the activity of both cytokines during aging. To do this, we use blocker antibodies in the face of the function of both cytokines for three months, in mice that were aging until they were old (Figure 3). After this, we analyzed the skin of these old treaties, discovering that much of the inflammation that previously existed in the aged dermis and epidermis was no longer present. With this, we were able to confirm that these cytokines have great relevance in the generation of the skin inflammatory context associated with age, which can be reduced by blocking its function over time.
Figure 3. Graphic description of the procedure followed to block the function of IL-17A and IL-17F. We neutralize the function of these cytokines through the use of antibodies that recognize and join both, preventing them from carrying out their function. This was done in mice that were aging, for three months and until they had already aged.
Next, we analyze whether this neutralizing treatment in the face of the action of IL-17A and IL-17F had affected the integrity and characteristics of the skin. To do this, we first check if skin permeability in old animals treated with antibodies had changed with treatment. Surprisingly, the skin of these aged and treated animals with blockers against IL-17A and IL-17F had an impermeability similar to that of young mice, instead of resembling other old animals of the same age in which neutralized the action of these cytokines. In the same way, animals treated with blocker antibodies for the two cytokines had more active hair follicles and stem cells, capable of growing hair also in a more similar way to young animals than to others aged. As for wound regeneration, animals treated with neutralizing antibodies also showed a healing of more efficient wounds compared to other old animals.
Therefore, the use of therapies that block the function of IL-17A and IL-17F could serve to slow down the appearance of characteristics of aging in the skin. However, it remains to be discovered what is the required amount of restriction of functions of these cytokines. Having an important function in the fight against external pathogens, its complete inhibition could lead to other problems. Therefore, it is necessary to find the balance between the blockade of its excessive action in aging, and its usual function, which is important to maintain the integrity of the skin . In this way, IL-17A and IL-17 levels could be reduced in the skin, reducing the deterioration of the skin associated with aging, but maintaining sufficient levels so that these cytokines carry out their antimicrobial function.
Conclusion
IL-17A and IL-17F inflammatory cytokines have roles related to the elimination of external pathogens in the skin, as in the development of chronic autoimmune and inflammatory diseases such as psoriasis. Now, we know that they are also crucial in cutaneous aging, since they are responsible for increasing inflammation associated with advanced age. In addition, we reveal its critical role in the development of the characteristics of aged skin, since the blocking of its function leads to the decrease in the appearance of these characteristics. Finally, the use of therapies that neutralize the function of these cytokines could be useful to slow down the skin.
References:
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