Neurotransmitters may fuel inflammatory flares in skin conditions

Immune-mediating neuropeptides may provide an avenue for addressing inflammatory skin diseases including psoriasis, said an expert at the 73rd American Academy of Dermatology Annual Meeting.

Richard D. Granstein, M.D.Richard D. Granstein, M.D., says, "Most patients and physicians believe that stress influences many inflammatory skin diseases. It is said that psoriasis, rosacea and acne all get worse with stress. This is a clinical impression; I believe it's almost certainly true." He is the George W. Hambrick, Jr., Professor and chairman of the department of dermatology at Weil Cornell Medical College.

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Several studies support this impression anecdotally, he adds, but controlled studies are rare: "Where do you find a control group that's not under stress?"

Soft data

One report showed that, after a large earthquake in Japan, the likelihood of atopic dermatitis (AD) flares rose in proportion to the severity of local damage.¹ Dr. Granstein says that potential confounding variables include the fact that "perhaps people in the earthquake zone did not apply their ointments or creams because they had other things to worry about."

Other studies show that combining pharmacological treatment with stress reduction interventions clears psoriasis faster than medical interventions alone, he says. Regarding AD, NC/Nga mice raised in a normal environment develop an itchy, eczema-like rash. Those raised in a cleaner, specific pathogen-free setting do not, unless exposed to psychological stress.²

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Dr. Granstein says, "These are soft data. Nonetheless it all supports the idea that certain inflammatory skin diseases worsen with stress. The question is, how?"

Several laboratory studies elucidate mechanisms by which nerves may influence inflammatory skin disease, says Dr. Granstein. The observation in humans and certain animal models that denervating (either surgically or phamacologically) psoriatic skin resolves the psoriasis has been known since the 1970s, he says, "But people don't talk about it much." Although psoriasis certainly involves the immune system, he says that "the nerves contribute something." Further support for this idea comes from clinical reports suggesting that botulinum toxin can clear psoriasis,³ says Dr. Granstein.

NEXT: Pathogensis clues

Pathogenesis clues

More recently, he says, "Our laboratory has demonstrated that 2 neuropeptides-pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal polypeptide (VIP)⁴-influence Langerhans cells to present antigen preferentially for generation of Th17 cells and interleukin (IL)-17 production," both of which are involved in the pathogenesis of psoriasis.

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"If stress causes release of PACAP and VIP from nerves in the skin," he surmises, "this may cause the outcome of local immune responses to be skewed towards IL-17, which one might imagine could make psoriasis worse." Because lymph nodes are innervated, he adds, "Perhaps antigen presentation occurring within the lymph nodes could also be affected."

Furthermore, an unpublished in vitro study co-authored by Dr. Granstein suggests that the neuropeptide calcitonin gene-regulating peptide (CGRP) can also influence the outcome of antigen presentation-not directly, but through the effects of endothelial cells.⁵ The dermatologist says that, "If we treat endothelial cells with CGRP, then wash out the CGRP, when in the presence of Langerhans cells and responding T cells, those endothelial cells are also able to influence the outcome of antigen presentation towards IL-17."

This is important, Dr. Granstein says, because blood vessels in the skin are innervated (by nerves that contain CGRP) and lined with endothelial cells. Also, he says, “norepinephrine, which is the principal neurotransmitter of the sympathetic nervous system, has the same effect as CGRP on endothelial cells. So certainly one would imagine that under periods of stress, as the sympathetic nervous system is activated as part of the fight-or-flight reaction, norepinephrine will be released and could influence endothelial cells" to skew antigen presentation toward IL-17.

NEXT: Potential contributors

Potential contributors

Regarding other potential contributors, says Dr. Granstein, "we've shown, for example, that although adenosine triphosphate (ATP) is important in the energy chain, it also is an extracellular messenger. And in fact, it's a sympathetic co-transmitter-it comes out with norepinephrine when sympathetic nerves are activated."⁶ ATP can induce endothelial cells to release chemokines that may attract certain inflammatory cells and IL-6, he notes. "So in this way, activation of the nervous system may nonspecifically amplify inflammation in the skin. In this scenario, under stress, the sympathetic nervous system is activated; ATP is released and binds to receptors on endothelial cells. This causes release of chemokines that allow for the accumulation of inflammatory cells," Dr. Granstein says.

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Also of interest, a recent paper reported that sensory nerves involved with pain sensation were needed for the development of psoriasiform inflammation in a mouse model of skin inflammation caused by a topically applied immune stimulator.⁷  In this report, the nerves appeared to induce release of the cytokine IL-23 from dendritic cells in the dermis; IL-23 is important in inducing IL-17 production by other cells, says Dr. Granstein, and it was reported to induce IL-17 release by a class of lymphocytes known as gamma-delta T cells. Whether stress would activate this pathway is unknown, he adds.

Some of the above pathways might provide drug targets, says Dr. Granstein, adding that "if one could imagine a way to block the effect of some of these neurotransmitters only in the skin and not in the rest of the body-perhaps with a cream, which would have negligible systemic absorption-this might be useful."

For clinicians treating inflammatory skin conditions such as psoriasis or AD in patients who believe that stress is contributing to the disease, Dr. Granstein says that "it's reasonable to recommend as part of the therapeutic armamentarium interventions to relieve stress." Examples include relaxation techniques, support groups and perhaps, where appropriate, counseling or psychotherapy. "It's reasonable for another reason-although stress may cause disease, disease causes stress. Psoriasis and AD are uncomfortable and often itchy. Sometimes people are disturbed by the appearance of their skin with these diseases. There are many reasons why measures to try to deal with stress may be useful" in combating skin disease, says Dr. Granstein..

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Ultimately, he says, "You don't need to postulate any of these mechanisms. If a patient says, 'when I have trouble at work, my psoriasis flares,' that's all you need to know."

Disclosures: Dr. Granstein has been a consultant (fee) for Galderma, a consultant (no compensation) for Kolltan and an advisory board member (no compensation) for Velius.

References

1. Kodama A, Horikawa T, Suzuki T, et al. Effect of stress on atopic dermatitis: investigation in patients after the great hanshin earthquake. J Allergy Clin Immunol. 1999;104(1):173-6.

2.  Amano H, Negishi I, Akiyama H, Ishikawa O. Psychological stress can trigger atopic dermatitis in NC/Nga mice: an inhibitory effect of corticotropin-releasing factor.Neuropsychopharmacology. 2008;33(3):566-73.

3.  Gilbert E, Ward NL. Efficacy of botulinum neurotoxin type A for treating recalcitrant plaque psoriasis.J Drugs Dermatol. 2014;13(11):1407-8.

4. Ding W, Manni M, Stohl LL, Zhou XK, Wagner JA, Granstein RD. Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells. Eur J Immunol. 2012;42(4):901-11.

5. Granstein RG. Is stress causing my skin disease? Presented at: American Academy of Dermatology Summer Academy; August 6-10, 2014; Chicago.

6. Stohl LL, Zang JB, Ding W, Manni M, Zhou XK, Granstein RD. Norepinephrine and adenosine-5'-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells. Cytokine. 2013;64(2):605-12.

7. Riol-Blanco L, Ordovas-Montanes J, Perro M, et al. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature. 2014;510(7503):157-61.