The brain–skin connection: role of psychosocial factors and neuropeptides in psoriasis

Figure 1. Stress, genetics and the upregulation of neuropeptides in the skin contribute to the inflammatory response underlying psoriasis.

Furthermore, psoriasis can be associated with a systemic inflammatory response [25–28], which could exacerbate negative psychosocial states, resulting in high levels of anxiety and depression [7–13].

ACTH: Adrenocorticotropic hormone; CGRP: Calcitonin gene-related peptide; CRH: Corticotrophin-releasing hormone; GC: Glucocorticoid; NGF: Nerve growth factor; VIP: Vasoactive intestinal peptide.

Decades of research have provided data to confirm the hypothesis that there is bidirectional communication between the CNS 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 downregulated by these neurochemicals. As one example, endogenous catecholamines can bind to β2-adrenergic receptors on unstimulated CD4⁺ T cells, resulting in a decreased production of IFN-γ and increased production of IL-4 following stimulation through the T-cell receptor (reviewed in [1]).

In addition, there is a large body of 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 in [2]). Numerous investigators have observed that stress [3–5] 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 proinflammatory cytokines can induce depressive symptoms [7–11] and increase anxiety [12,13] in both rodents and humans.

In addition to the role of the psychological state on immune function, stable psychological traits may also be correlated with the magnitude of an immune response or with the 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, minority groups 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. In addition, our group has shown that neuroticism – or chronic predisposition to emotional distress – is an even greater correlate of IL-6 than a state of depression in patients with end-stage renal disease [Chapman BP, Juskiewicz I, Schiff M et al., Unpublished data].

The fact 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 the metabolic syndrome [16–18]. However, the contribution of the psychological state/personality traits to inflammatory processes may possibly be a tipping point for the progression of or flares of immunologically mediated inflammatory diseases. Here, we consider the role of negative psychosocial factors in the skin disease psoriasis (Figure 1).

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 Th1 and Th17 cytokine networks in the development of psoriatic lesions. Within this network, cytokines, including IL-6, drive the maturation of naive T cells into Th17 cells. Once activated, Th17 cells attract neutrophils to the tissue site [20]. IFN-γ and 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 [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 the metabolic syndrome [25–28].

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 [33–36]. High expression of NGF, for example, mediates T-cell and keratinocyte proliferation, mast cell migration, degranulation and memory T-cell chemotaxis, which are all hallmarks of psoriasis [33,37,38].

Unsurprisingly, psoriasis patients commonly report a significant decrease in their quality of life, as well as 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]). More than 40% of patients meet criteria for probable mood disorders [40], and the prevalence of depression and/or anxiety disorders is reported as ranging from 30% [41] to as much 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 of the disease [42,44].

Such heightened levels of distress in psoriasis patients are likely to affect the 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, adrenocorticotropic hormone 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 were observed in the papillary dermis of lesional skin by immunohistochemistry; such nerve fibers were barely detectable in lesions from low-stress individuals [46]. Furthermore, 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. For example, Fortune et al. showed that a short program of cognitive behavioral therapy was associated with a decrease in the number and frequency of psoriasis symptoms reported, even 6 months following the program’s end [50]. It should be noted that this was not a randomized, controlled trial; patients were allowed to choose cognitive behavioral therapy. 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 the study were that subjects treated with MBSR and UVB cleared their lesions in 83 days on average compared to 113 days for subjects receiving UVB alone; for those treated with MBSR plus PUVA, clearance occurred in 48 days, compared to 85 days for individuals treated with PUVA alone [52].

Thus, the inflammatory disease psoriasis provides strong evidence for the relationships between 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 the psychological wellbeing in this population of patients who duffer from high stress levels and depression may be particularly well suited for dampening the inflammatory response.

Financial & competing interests disclosure

This work was supported by grants R21AG023956 (Jan Moynihan), 1R24AG031089-01 (Jan Moynihan) and K08AG031328 (Ben Chapman) from the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.