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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Expert Rev Clin Immunol. Author manuscript; available in PMC 2010 August 24.
Published in final edited form as:
PMCID: PMC2926975

The Brain-Skin Connection: Role of Psychosocial Factors and Neuropeptides in Psoriasis

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 experiments—leading to the early hypothesis that the immune system functions autonomously—it 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 β2-adrenergic receptors on unstimulated CD4+ T cells, resulting in decreased production of interferon (IFN)-γ 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 sociability—had higher circulating levels of IL-6. Gender 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 neuroticism—or chronic proneness to emotional distress—is 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).

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 systemic inflammatory response(25,26,27,28) which could exacerbate negative psychosocial ...

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 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 naïve T cells into Th17 cells. Once activated, Th17 cells attract neutrophils to the tissue site(20). IFN-γ and tumor necrosis factor (TNF)-α 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). 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-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 was significantly increased, and neutralization of NGF in this model abrogated the increased expression(47).

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. Psychotherapy—including stress reduction and imagery—was 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 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.


This work was supported by R21AG023956 (JM), 1R24AG031089-01 (JM), and K08AG031328 (BC) from the National Institutes of Health.


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