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Comunicación cerebro-piel: el estrés

Communication brain-skin: stress mediators

We are sure that, based on our previous posts, you already know that the skin is not a mere wrapping of the body, in charge only of isolating the internal organs from the outside. The skin is a complex organ that has numerous functions including an important immune role and a relevant and complex sensory function.

In recent decades, a multitude of data have been collected showing the existence of powerful brain-skin communication. Something as simple as feeling cold and putting a jacket on demonstrates the fast and effective communication that exists between the skin and the brain. When the outside temperature drops, the thermal receptors (thermoreceptors) that accumulate in the epidermis are able to perceive it and induce changes that “alert” the nerve endings. They quickly transfer the information to the spinal cord and brain, which is responsible for articulating the final response: generating the need to shelter and giving orders to the motor nerves to put a jacket on. This doesn’t just happen with temperature changes. There are other types of receptors such as nociceptors (capable of perceiving pain), or mechanoreceptors (responsible for detecting mechanical changes) that are responsible for transmitting changes that occur outside the central nervous system in order to induce an adaptive response. Quickly putting your hand away when we prick ourselves with a cactus or launch an immune response when detecting a pH change due to an infection, are other examples of the effective role of the skin as part of the nervous system (1,2).

However, this communication is not one-way. It is becoming increasingly evident that changes affecting the central nervous system have a response in the skin. A clear example of this is stress.

Stress occurs when the individual perceives that the pressure to which he or she is subjected to, regardless of the element causing this pressure, exceeds his adaptive power. In these circumstances the brain releases hormones (such as glucocorticoids, corticoliberin or epinephrine) that induce a number of physiological and behavioral changes aimed at adapting our body to the stress situation. This response must be controlled since having an excessive or inadequate stress response can lead to adverse physiological effects. In fact, stress has been shown to induce or worsen cardiovascular or autoimmune diseases, migraine, neurodegeneration, skin problems… (3-7).

Surprisingly, recent studies have confirmed that the skin functions work both as a target of the stress response initiated by the central nervous system, as well as an effector agent, capable of perceiving this stress and initiating an adaptive response. In fact, the skin has a fully functional peripheral system equivalent to the hypothalamic-pituitary-adrenal axis. In addition, serotonin, which is a classic neurotransmitter with a crucial role in the central nervous system, also plays an essential role in the skin acting as a mediator between this organ and the neuroendocrine system (7).

Next, let’s talk about the main molecules that are released in response to the stress and their function when they are synthesized or released in the skin.

Cortisol

When we are under stress, the hypothalamus, an essential part of our brain, sets in motion a response that involves interaction with other parts of the brain and that leads to the release of cortisol and corticosterone. Both hormones make up the primary response of our body to stress. Normally, cortisol levels oscillate on a regular basis throughout the day reaching maximum concentration peaks in the morning, when waking up, and minimum levels at night. This allows us to “activate” ourselves and carry out our daily tasks. Stress can modify this cycle by increasing cortisol levels or displacing the maximum and minimum curve, which alters our natural rhythm (8).

Interestingly, some skin cells, such as keratinocytes, melanocytes, or sebocytes, are also able to synthesize cortisol precursor molecules in stressful situations such as skin pathology or ultraviolet [UV] radiation (9).

Adrenaline and noradrenaline

Other important stress mediators are epinephrine (adrenaline) and norepinephrine (noradrenaline). Both hormones are critical components of the “fight or flight response”, typical of stressful situations where life is in danger. This type of response is characterized by increased heart and breathing rate, constriction of blood vessels except muscle vessels, pupil dilation and increased perspiration.

Let’s imagine that all of a sudden, walking through the woods, we come across a hungry bear. This clear stressful situation in which we feel our life is in danger stimulates the rapid release of adrenaline. The physiological changes discussed above facilitate that more blood reaches our muscles and that we can run faster to avoid the imminent danger of being caught by the bear. Today, such situations are not as common, but the brain reacts in the same way to non-everyday situations that we perceive as difficult or dangerous such as an exam, an interview or an accident.

As in the previous case, it has been observed that some cells in the skin are also capable of synthesizing and releasing adrenaline, which in turn can interfere with dermal health. In melanocytes, the adrenaline produced by the surrounding keratinocytes can promote melanin synthesis, resulting in blemishes or darkening of the skin. On the other hand, adrenaline can alter the synthesis of collagen carried out by fibroblasts, which affects the healing process (9).

Neurotrophins, Prolactine and Substance P

These substances are released by nerve endings that populate the skin and act as local stress mediators inducing different responses such as allergic inflammation. In addition, depending on the cell on which they act they can perform different functions. For example, neurotrophins protect keratinocytes from UV-induced death, increase fibroblast proliferation, which is essential for wound healing, or protects melanocytes from oxidative stress (9, 10).

Prolactin, on the other hand, is known to play an important role during pregnancy and lactation. However, when synthesized in the skin in response to stress it can regulate the expression of keratin, hair growth and stimulate fat production in the sebaceous glands. Moreover, it is thought to have a significant immune function in stressful situations as it seems to maintain the survival of lymphocytes (11).

Substance P is a neuropeptide, that is, a molecule secreted by cells in the nervous system, related to inflammation in stress situations. It is a key molecule that connects the brain to the hair follicles. In fact, animal models have shown that it can participate in inhibiting hair growth in stressful situations. In addition, it can increase the virulence of skin bacteria which increases its pro-inflammatory role (12).

Mast cells

Mast cells are immune cells that perform important defensive work against bacteria, parasites, and poisons in addition to participating in allergic reactions, arthritis or anaphylaxis. In stress situations, the main response routes, such as those mentioned above, end up inducing changes in the function of mast cells, which makes them be considered as the main mediators of the response to stress on the skin (9, 13).

In conclusion, under stress situations not only the brain is able to implement a response by releasing hormones and molecules. According to a recent research, the skin is also an important producer of such molecules that can exert their action locally by increasing inflammation and affecting biological functions such as healing or hair growth.

REFERENCES

  1. Schmelz M. Neuronal sensitivity of the skin. Eur J Dermatol. 2011 May;21 Suppl 2:43-7.
  2. Slominski AT, Zmijewski MA, Skobowiat C, Zbytek B, Slominski RM, Steketee JD. Sensing the environment: regulation of local and global homeostasis by the skin’s neuroendocrine system. Adv Anat Embryol Cell Biol. 2012;212:v, vii, 1-115.
  3.  Sandrini L, Ieraci A, Amadio P, Zarà M, Barbieri SS. Impact of Acute and Chronic Stress on Thrombosis in Healthy Individuals and Cardiovascular Disease Patients. Int J Mol Sci. 2020 Oct 22;21(21):E7818.
  4. Ilchmann-Diounou H, Menard S. Psychological Stress, Intestinal Barrier Dysfunctions, and Autoimmune Disorders: An Overview. Front Immunol. 2020 Aug 25;11:1823.
  5. Peña-Bautista C, Casas-Fernández E, Vento M, Baquero M, Cháfer-Pericás C. Stress and neurodegeneration. Clin Chim Acta. 2020 Apr;503:163-168.
  6. Madore C, Yin Z, Leibowitz J, Butovsky O. Microglia, Lifestyle Stress, and Neurodegeneration. Immunity. 2020 Feb 18;52(2):222-240.
  7. Martins AM, Ascenso A, Ribeiro HM, Marto J. The Brain-Skin Connection and the Pathogenesis of Psoriasis: A Review with a Focus on the Serotonergic System. Cells. 2020 Mar 26;9(4):796.
  8. Weitzman ED, Fukushima D, Nogeire C, Roffwarg H, Gallagher TF, Hellman L. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab. 1971 Jul;33(1):14-22.
  9. Chen Y, Lyga J. Brain-skin connection: stress, inflammation and skin aging. Inflamm Allergy Drug Targets. 2014;13(3):177-90.
  10. Marconi A, Terracina M, Fila C, Franchi J, Bonté F, Romagnoli G, Maurelli R, Failla CM, Dumas M, Pincelli C. Expression and function of neurotrophins and their receptors in cultured human keratinocytes. J Invest Dermatol. 2003 Dec;121(6):1515-21.
  11. Langan EA, Hinde E, Paus R. Prolactin as a candidate sebotrop(h)ic hormone? Exp Dermatol. 2018 Jul;27(7):729-736.
  12. Peters EM, Arck PC, Paus R. Hair growth inhibition by psychoemotional stress: a mouse model for neural mechanisms in hair growth control. Exp Dermatol. 2006 Jan;15(1):1-13.
  13. Theoharides TC. The impact of psychological stress on mast cells. Ann Allergy Asthma Immunol. 2020 Oct;125(4):388-392.
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