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The Brain Skin Connection

Now that evidence of a relationship between the autonomic nervous system and seborrheic dermatitis has been presented, let’s try to decipher the specific mechanism in which the brain and skin interact. Understanding this mechanism should provide the perspective needed to not only better understand the relationship, but also give the foundational framework for implementing beneficial changes.

The brain communicates with the skin via something that has been termed as the neuro-immunoendocrine system. The word neuro-immunoendocrine can sound quite daunting, but it’s meaning is simple: the interaction between the nervous system and the immune system (the skin being an immune system organ).

Consequently, this section will investigate how this circuitry operates and how the two systems interact.

Examination of the Stress Response for Clues

One of the most explored areas in this line of research is how our bodies respond to stress. And the most common way for researchers to study this connection has been through mice (poor mice).

In these animal models, the mice are placed under stressful conditions (loud sounds, bright lights, etc.) and researchers monitor how their organisms respond. The whole approach is undoubtedly cruel, but it has allowed humans to gain a much better understanding of how our own bodies operate under similar conditions.

In stressed mice, the production of several inflammatory substances is induced via a hierarchical pathway (one leading to the next) [1].

The key components of this pathway are (in hierarchical order):

  • Corticotropin-releasing hormone
  • Nerve growth factor
  • Neurotensin
  • Substance P
  • Mast cells

As this process progresses, getting closer to the concluding components (Substance P and mast cell activation), the chance for dermatological damage increases; these later stages drive significant inflammation, which dissipates and impacts other nearby components of the immune system.

A difficult relationship to unravel
While it’s difficult to determine if the stress can cause dermatitis to appear in the first place, it has been demonstrated that it can drastically worsen existing dermatitis [2, 3].

A similar mechanism has been described in humans and researchers have theorized that abnormal activation of any individual part of the process may serve as the foundation for a variety of chronic inflammation driven skin conditions [4, 5, 6, 7, 8].

Why the Skin is So Prone to Neural Influences

Since the skin comes into direct contact with the outside environment, our skin is also a site of dense and intricate innervation (networks of nerves) [5]. And these delicate sensory nerve endings need to be sensitive to both our external environment and internal environments; being able communicate external stimuli to the brain (in case of local issues – such as a wound) and being receptive to incoming signaling from our brain (in the case where issues at other sites require more nutrients/resources – fighting off an infection).

Returning to the animal model (mouse) of chronic stress, it is well established that many of the primary features of stable immune response become impaired; specifically an abnormal ratio of Th1 to Th2 and reduced Treg cell expression []. This impairment is so significant that it’s been shown to be capable of severely inhibiting hair growth and driving excessive skin inflammation in the animals being studied [9, 10, 11].

Putting this in context, it means that without any external pathogens or irritants, the skin of these animals was severally degraded simply through the activity of the nervous system (as a response to psychological stressors) and it’s interaction with the immune system. Put more bluntly: stable skin function depends on stable nervous system function.

Focusing in on Mast Cells and Nerve Growth Factor

Undoubtedly, the communication between the central nervous system and the skin (including neurotransmitter, neuropeptides, neutrophils, and neurohormones) is significantly more complex than the general 5 step hierarchy outlined briefly above. Understanding it in its entirety could very well be highly valuable, but one may also gain a significant benefit from understanding two components that appear to be most directly involved with skin inflammation.

These components are:

  • Mast cells
  • Nerve growth factor

Mast Cells and Their Involvement in the Inflammatory Response

Mast cells appear to be at the center stage of our skins ability to communicate between the nervous system and the local immune system. Mast cells are responsible for activating a myriad of inflammation-driven immune responses (histamine, cytokines, tumor necrosis factor-a, vascular endothelial growth factor, and several others).

These cells are of particular interest to skin disease since they are:

  • Positioned in close proximity to both nerves and blood vessels.
  • Able to modulate both the innate immune response and the adaptive immune response.
  • Act as a communication pathway between the immune response and the nervous system.

Their pivotal role is probably best demonstrated by the effectiveness of corticosteroids in reducing inflammation and eliminating skin symptoms for the large majority of skin conditions. Corticosteroids work by inhibiting mast cell activation []. As the mast cells become inhibited, the inflammatory response is halted and the associated symptoms rapidly resolve, leading to symptom relief.

Mast cells are also required for the repair process
Corticosteroids are the most commonly prescribed topical agents for the treatment of seborrheic dermatitis. They work almost instantly and provide significant relief. However, long term use can impair the normal process of epidermal repair by driving away mast cells altogether [12].

While diminishing mast cell activation is one way to approach treatment, determining the source of overactive mast cells may be a more permanent solution. Since mast cells are near the end of the hierarchy chain discussed earlier, if we are able to understand what’s causing the over-activity in the first place, we may be able to stop the process from spiraling out of control in the first place.

Mast cells can be activated in a variety of ways:

  • IgE and antigens
  • Cytokines
  • Hormones
  • Neuropeptides

Now since we are talking about the nervous system, the most interesting of these to our discussion is the last one: neuropeptides – a specific type of peptides responsible for orchestrating the communication and development of neurons.

Nerve Growth Factor

Nerve growth factor (NGF) is one of these neuropeptides (that can activate mast cells) and its primary role is described in its name: regulation and maintenance of neurons [13]. Its release by glial cells can rapidly be triggered by stress [9] and it has the peculiar ability to promote mast cell production and survival [14].

Interestingly, inhibition of nerve growth factor reverses the negative effects of stress on both hair growth and inflammation [9]. And this appears to be related to the ability of nerve growth factor to regulate Substance P production (a pain molecule) [15], which then goes onto control mast cell activation [11].

Research of NGF has shown that chronic stress can increase the amount of nerve growth factor circulating through our bodies []. This, in turn, may be resulting in overactivation of the nervous system fueling a state of overexpansion. As the system stumbles out of its regular state of homeostasis (balance), mast cell activation also spirals out of control. The end result of this process could very well be excessive – yet not properly developed – innervation in the epidermis.

While the above is just a theory, the plausibility of such mechanism has been described in the case of atopic dermatitis [16] and would in-part explain the beneficial impact of ultra-violet based therapies (a therapy that decreases epidermal nerve density [17]).

Section Summary

This section further evaluated the connection between the nervous system and the skin. It also introduced some potential areas which may be the key to understanding the mechanism which translates nervous system problems to skin issues down the line.

Key points include:

  1. The communication of the nervous system and the skin is scientifically referred to as the neuro immunoendocrine system; more broadly, it’s the relationship between the nervous system and the immune system
  2. Studies which examine the stress response of both animals and humans, and how this impacts skin function, provide the primary clues in this area of research
  3. Periods of high stress and activation of the sympathetic nervous system can induce inflammation via process composed of several individual steps
  4. The steps occur in a linear fashion (one after the other) and the longer the processed is allowed to continue – the greater the amount of inflammation
  5. Issues and instability at any stage of this process could potentially lead to abnormal levels of inflammation, eventually inducing dermatological damage
  6. The skin is very susceptible to being damaged by over-activation of this pathway due to the high amount and density of nerve-endings present
  7. Mast cells and nerve growth factor have garnered the most attention when it comes to nervous system related skin issues
  8. Mast cells are at the final stages of this process and carry much of the responsibility for activating inflammation; corticosteroids work by inhibiting mast cell activity
  9. Nerve growth factor is at the beginning stages of this process and it’s over-activity has been proposed as the key driver of skin inflammation, UV therapy is believed to work by inhibiting nerve growth

References

  1. Ralf Paus, Theoharis C Theoharides, Petra Clara Arck "Neuroimmunoendocrine circuitry of the ‘brain-skin connection’." Trends in immunology 27.1 (2006): 32-9. PubMed
  2. Sanja Pavlovic, Maria Daniltchenko, Desmond J Tobin, Evelin Hagen, Stephen P Hunt, Burghard F Klapp, Petra C Arck, Eva M J Peters "Further exploring the brain-skin connection: stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice." The Journal of investigative dermatology 128.2 (2008): 434-46. PubMed
  3. Christiane Liezmann, Burghard Klapp, Eva Mj Peters "Stress, atopy and allergy: A re-evaluation from a psychoneuroimmunologic persepective." Dermato-endocrinology 3.1 (2011): 37-40. PubMed
  4. Dirk Roosterman, Tobias Goerge, Stefan W Schneider, Nigel W Bunnett, Martin Steinhoff "Neuronal control of skin function: the skin as a neuroimmunoendocrine organ." Physiological reviews 86.4 (2006): 1309-79. PubMed
  5. Ralf Paus, Theoharis C Theoharides, Petra Clara Arck "Neuroimmunoendocrine circuitry of the ‘brain-skin connection’." Trends in immunology 27.1 (2006): 32-9. PubMed
  6. Verena D Schwab, Mathias Sulk, Stephan Seeliger, Pawel Nowak, Jerome Aubert, Christian Mess, Michel Rivier, Isabelle Carlavan, Patricia Rossio, Dieter Metze, Jörg Buddenkotte, Ferda Cevikbas, Johannes J Voegel, Martin Steinhoff "Neurovascular and neuroimmune aspects in the pathophysiology of rosacea." The journal of investigative dermatology. Symposium proceedings 15.1 (2012): 53-62. PubMed
  7. Ilkka T Harvima, Gunnar Nilsson, Mireille-Maria Suttle, Anita Naukkarinen "Is there a role for mast cells in psoriasis?" Archives of dermatological research 300.9 (2008): 461-78. PubMed
  8. Andrea L Suárez, Jamison D Feramisco, John Koo, Martin Steinhoff "Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates." Acta dermato-venereologica 92.1 (2012): 7-15. PubMed
  9. Eva Milena J Peters, Bori Handjiski, Arne Kuhlmei, Evelin Hagen, Hannes Bielas, Armin Braun, Burghard F Klapp, Ralf Paus, Petra Clara Arck "Neurogenic inflammation in stress-induced termination of murine hair growth is promoted by nerve growth factor." The American journal of pathology 165.1 (2004): 259-71. PubMed
  10. P C Arck, B Handjiski, E Hagen, R Joachim, B F Klapp, R Paus "Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15.13 (2001): 2536-8. PubMed
  11. Petra Clara Arck, Bori Handjiski, Eva Milena J Peters, Anita S Peter, Evelin Hagen, Axel Fischer, Burghard F Klapp, Ralf Paus "Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways." The American journal of pathology 162.3 (2003): 803-14. PubMed
  12. R M Lavker, N M Schechter "Cutaneous mast cell depletion results from topical corticosteroid usage." Journal of immunology (Baltimore, Md. : 1950) 135.4 (1985): 2368-73. PubMed
  13. R Levi-Montalcini "The nerve growth factor: thirty-five years later." The EMBO journal 6.5 (1987): 1145-54. PubMed
  14. J S Marshall, K Gomi, M G Blennerhassett, J Bienenstock "Nerve growth factor modifies the expression of inflammatory cytokines by mast cells via a prostanoid-dependent mechanism." Journal of immunology (Baltimore, Md. : 1950) 162.7 (1999): 4271-6. PubMed
  15. Anne M Skoff, Joshua E Adler "Nerve growth factor regulates substance P in adult sensory neurons through both TrkA and p75 receptors." Experimental neurology 197.2 (2006): 430-6. PubMed
  16. Mitsutoshi Tominaga, Kenji Takamori "Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications." The Journal of dermatology 41.3 (2015): 205-12. PubMed
  17. Mitsutoshi Tominaga, Suhandy Tengara, Atsuko Kamo, Hideoki Ogawa, Kenji Takamori "Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and modulates epidermal innervation in atopic dermatitis." Journal of dermatological science 55.1 (2009): 40-6. PubMed
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About Michael Anders

After being affected by seborrheic dermatitis, I have made it my goal to gather and organize all the information that has helped me in my journey.

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