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Expert Rev Clin Immunol. 2009 November ; 5(6): 623627. doi:10.1586/eci.09.56.

The Brain-Skin Connection: Role of Psychosocial Factors and

Neuropeptides in Psoriasis

Ben P. Chapman and Jan Moynihan

Decades of research have provided the data to confirm the hypothesis that there is
bidirectional communication between the central nervous system and the immune system.
Although much of the important dogma in immunology has been largely predicated on in
vitro experimentsleading to the early hypothesis that the immune system functions
autonomouslyit is quite clear that lymphoid cells express receptors for a wide variety of
hormones/neurotransmitters, and that immune responses can be up- or down-regulated by
these neurochemicals. As but one example, endogenous catecholamines can bind to 2-
adrenergic receptors on unstimulated CD4+ T cells, resulting in decreased production of
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interferon (IFN)- and increased production of interleukin (IL)-4 following stimulation

through the T cell receptor (reviewed in(1)).

As well, there is a large literature documenting the effects of acute and chronic stress,
anxiety, and depression on innate and adaptive immune responses in both humans and
animal models (reviewed by(2)). Numerous investigators have observed that stress(3,4,5)
and depression(6) are associated with increased levels of circulating proinflammatory
cytokines, particularly IL-6. In turn, psychological distress may be amplified by the process
of inflammation itself, as the proinflammatory cytokines can induce depressive
symptoms(7,8,9,10,11) and increase anxiety(12,13) in both rodents and humans.

In addition to the role of psychological state for immune function, stable psychological traits
may also be correlated with the magnitude of an immune response or production of
inflammatory cytokines (which may or may not be immunologically-derived). For example,
in a community sample of healthy adults, antagonistic behavioral traits were associated with
significant elevations in plasma IL-6 and C-reactive protein (CRP)(14). Recent data from
our laboratory suggest that within a diverse urban primary care sample, women, minorities,
and patients lower in the personality trait of Extraversion--specifically, dispositional
activity, but not positive affect or sociabilityhad higher circulating levels of IL-6. Gender
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and race/ethnicity were determined to be important dimensions of group differences in IL-6

levels, but after these group differences were accounted for, dispositional activity remained
an important contributor to individual variability in IL-6(15). This phenotypic trait seems to
be a marker of energetic engagement with life, involving vigor, a busy and lively schedule,
and a love of external stimulation. As well, our group has shown that neuroticismor
chronic proneness to emotional distressis an even greater correlate of IL-6 than state
depression in patients with end stage renal disease (unpublished data).

That stress, depression, anxiety and personality traits have implications for inflammation--
even within relatively healthy adults--is important to consider, particularly in light of the
clear impact that long-term elevations of inflammatory cytokines and CRP have for diseases
of aging such as cardiovascular disease, diabetes, and metabolic syndrome(16,17,18).
However, the contribution of psychological state/traits to inflammatory processes may
possibly be a tipping point for progression of or flares in immunologically-mediated
inflammatory diseases. Here we consider the role of negative psychosocial factors in the
skin disease psoriasis (Figure 1).
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Immune regulation plays the central pathophysiological role in the development of psoriasis,
an autoimmune condition with a complex genetic basis(19). Psoriasis is characterized
histologically by increased proliferation of keratinocytes (the major cell type in the
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epidermis), and by inflammatory leukocyte cell infiltration into the epidermis and the
underlying dermis. Accumulating evidence currently points to a central role for the T helper
(Th)1 and Th17 cytokine networks in the development of psoriatic lesions. Within this
network, cytokines, including IL-6, drive maturation of nave T cells into Th17 cells. Once
activated, Th17 cells attract neutrophils to the tissue site(20). IFN- and tumor necrosis
factor (TNF)- derived either from Th1(21) or a subset of Th17 cells(22) are also elevated in
psoriatic lesions and act to amplify inflammation. The upregulation of the inflammatory
cytokines also results in concomitant increases in keratinocyte hyperproliferation(23,22,24).
New data are emerging to suggest that the inflammatory response may not be localized only
to the skin, but that psoriasis is also a systemic inflammatory disease associated with
increased risk for the development of obesity, insulin resistance, cardiovascular disease and
metabolic syndrome(25,26,27,28).

The skin is highly innervated, in accordance with its role as the diffuse brain(29). There is
an array of neuropeptides localized in the skin, which includes catecholamines, substance P,
calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and nerve
growth factor (NGF). Activation of the autonomic nervous system and increases in a variety
of neuropeptides in the skin are significantly correlated with psoriatic lesions(30,31).
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Evidence that psoriasis may be associated with dysregulation of the peripheral nervous
system originally came from the observation by Farber and colleagues that in patients who
suffered traumatic severance of sensory innervation, the psoriatic plaques in the areas
innervated by the sectioned nerves resolved, and only reappeared when nerve fibers
regenerated and the sensitivity returned(32). This observation highlights the role played by
sensory cutaneous nerves in psoriasis, leading to the hypothesis that locally secreted
neuropeptides contribute to the maintenance of psoriatic disease(32,33). Subsequently, it
was found that psoriatic plaques have increased nerve fiber density and increased expression
of a number of neuropeptides(34,35,33,36). High expression of NGF, e.g., mediates T cell
and keratinocyte proliferation, mast cell migration, degranulation, and memory T cell
chemotaxis, which are all hallmarks of psoriasis(33,37,38).

Not surprisingly, psoriasis patients commonly report a significant decrease in quality-of-life,

and a range of negative psychosocial consequences, including high rates of depression,
suicidal thoughts, increased perceived stress levels, social stigmatization, and employment
problems (reviewed in(39)). Upwards of 40% of patients meet criteria for probable mood
disorders(40), and prevalence of depression and/or anxiety disorder is reported as ranging
from 30%(41) to as many as 58% of subjects(42). Thus, psoriasis is not only an immune-
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driven disease, but is also often characterized by significant mental health issues.
Psychological or life stressors have been reported to precede the onset of psoriasis(43), as
well as to precipitate flares in the disease(44,42).

Such heightened levels of distress in psoriasis patients is likely to affect disease via stress-
responsive hormones released in the circulation or in the skin. Indeed, evidence is
accumulating to support the existence of a hypothalamo-pituitary-adrenal axis equivalent
within the skin, with stress triggering localized secretion of corticotrophin releasing
hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids (reviewed
in(45)). Harvima and colleagues observed that in those psoriasis patients categorized as
having high levels of psychological stress, elevated expression of VIP and CGRP was
observed in the papillary dermis of lesional skin by immunohistochemistry; such nerve
fibers were barely detectable in lesions from low-stress individuals(46). Further, in a mouse
model of stress, the number of nerve fibers in the dermis expressing substance P and CGRP

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 Chapman and Moynihan Page 3

was significantly increased, and neutralization of NGF in this model abrogated the increased
expression(47).
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Perhaps, then, patients with psoriasis who also report high levels of psychological distress
may benefit from either pharmacological or psychological interventions to reduce their
levels of distress. Numerous psychosocial interventions aimed at the reduction of stress have
proved to be successful for the treatment of psoriasis (as well as psychological symptoms).
Hypnosis is one alternative therapy with evidence of utility for these patients(48,49).
Psoriasis patients improved significantly during hypnosis sessions in which they received
suggestions that they were being exposed to whatever they believed would ameliorate
their condition.(48).

More traditional therapies have also been applied with some success to patients with
psoriasis. Fortune et al.(50), for example, showed that a short program of cognitive
behavioral therapy (CBT) was associated with a decrease in the number and frequency of
psoriasis symptoms reported even six months following the program's end. It should be
noted that this was not a randomized control trial (RCT); patients were allowed to choose
CBT. Psychotherapyincluding stress reduction and imagerywas also shown to have a
positive effect on disease activity(51). Finally, in one of the first trials of Mindfulness Based
Stress Reduction (MBSR) as an adjunct treatment for disease, Kabat-Zinn et al. recruited
adult patients with moderate to severe psoriasis (covering >15% of the body surface) who
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were prescribed ultraviolet (UV)B or psoralen (methoxypsoralen) in combination with

ultraviolet A irradiation (PUVA). The significant findings from this study were that the
average time to clearance of lesions with UVB for MBSR subjects was 83 days compared to
113 for the controls, and for PUVA, 48 days for the MBSR subjects, compared to 85 days
for the controls(52).

Thus, the inflammatory disease psoriasis provides strong evidence for the relationships
among psychological factors, the brain, the diffuse brain contained within the skin, and
disease. The bidirectionality of these interactions may, in turn, exacerbate levels of
depression and stress in the patient. Interventions targeted at improving psychological well-
being in this population of patients who endorse high stress and depression may be
particularly well-suited to dampening the inflammatory response.

Acknowledgments
This work was supported by R21AG023956 (JM), 1R24AG031089-01 (JM), and K08AG031328 (BC) from the
National Institutes of Health.
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Figure 1.
Stress, genetics and the upregulation of neuropeptides in the skin contribute to the
inflammatory response underlying psoriasis. Further, psoriasis can be associated with a
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systemic inflammatory response(25,26,27,28) which could exacerbate negative psychosocial

states, resulting in high levels of anxiety and depression(713).

Expert Rev Clin Immunol. Author manuscript; available in PMC 2010 August 24.