¹Institute for Cell Biology and Neurobiology, Center for Anatomy, Charité–Universitätsmedizin Berlin, Germany

Correspondence: Dr Sven Hendrix, Institute for Cell Biology and Neurobiology, Center for Anatomy, Charité–Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany. E-mail: sven.hendrix@charite.de

Abstract

The precise nature of the link between stress and exacerbation of skin inflammation has puzzled researchers and clinicians alike. The traditional explanation is that immune balance is altered by activation of two stress axes: activation of the hypothalamic–pituitary–adrenal (HPA) axis raises cortisol levels, and activation of the sympathetic nervous systems raises adrenaline levels (Figure 1). In this issue, Pavlovic et al. (2008) provide evidence for a third stress axis and report that stress travels to the skin through peripheral neuropeptidergic nerve fibers and exacerbates the neurogenic inflammatory aspect of cutaneous dermatitis. Clarification of the role of this alternative stress axis may enable the design of novel therapeutic strategies

Figure 1.

Three stress axes exacerbating inflammatory skin disease. HPA, hypothalamic-pituitary-adrenal axis; TH2, T helper cell type 2 cytokine milieu.

Full figure and legend (80K)

Pathologies that involve chronic relapse and significant discomfort, such as atopic dermatitis, are regarded as psychosomatic dermatoses (Wright et al., 2005). In the early days of psychoanalysis, the skin was regarded as one vehicle by which the body and soul express the feelings and well-being of its bearer. Itchy and inflamed skin was interpreted as a cry for attention and help and a sign of severe deprivation of tenderness and care.

In the past, the close interaction between neuropeptidergic nerve fibers and immune cells in the skin was widely understood as playing a role in the cutaneous stress response. Altered nerve-fiber counts in atopic dermatitis, psoriasis, nummular eczema, and many other—mostly chronic and inflammatory—skin pathologies were viewed as evidence of the possible influence of stress on the course of inflammation.

In parallel, stress research provided evidence of a close interaction between nerve fibers and, for example, mast cells under stress (ranging from physical to psychological) (Theoharides and Cochrane, 2004). The idea that mast cells are activated under conditions of stress in exacerbated inflammatory skin disease became accepted almost to the point of textbook knowledge, even though experimental evidence has still not been provided.

Initial insights into the pathogenesis of stress-induced exacerbation of cutaneous inflammation were provided by studies showing a decreased acute excitability of the HPA axis and chronically elevated basal levels of cortisol (Buske-Kirschbaum et al., 2001). Such an imbalance in the stress response is commonly associated with an imbalance in the immune response, with a predominance of so-called T helper cell type 2 cytokines, such as interleukin-4 and -5. Because this constellation was observed in both chronically stressed and atopic dermatitis patients, it was hypothesized that chronic stress exposure facilitates allergy development. On the other hand, frequently observed exacerbation after exposure to acute stress remained unexplained.

The study by Pavlovic and colleagues provides the first complex experimental evidence that stress influences skin homeostasis via peripheral neuropeptidergic nerve fibers, which in turn activate mast cells by secreting neuropeptides such as substance P ("neurogenic inflammation"). Mast cell degranulation provides multiple mediators that activate endothelial cells, leading to effects such as the development of erythema and edema. Thus, neurogenic inflammation exacerbates cutaneous dermatitis.

The authors have demonstrated a plausible chain of events that goes a long way toward explaining to physicians and their patients the role of stressful life events in the exacerbation of inflammatory skin disease. Furthermore, this concept helps to focus research on a third stress axis, which may be therapeutically manipulated. However, the role of T helper cells in this new hypothesis could be understated because these may play a key role in modulating cutaneous neuronal plasticity (and, as a consequence, neurogenic inflammation as well) via secreted factors such as cytokines and neurotrophins (Hendrix and Nitsch, 2007). It will be particularly interesting to see whether the cardinal symptom of neurogenic inflammation—itch—can also be therapeutically influenced by antagonists to the substance P receptor neurokinin-1.

The organs protecting the borders of our body, such as skin, lung, or gut, which are frequently challenged by a wide variety of stressors, are characterized by dense innervation. Therefore, similar interactions between peripheral nerve fibers and targeted mast cells, as shown in skin by Pavlovic and colleagues, may also account for stress effects in other potentially stress-sensitive organs. Thus, a third stress axis has been added to the two classical models that has equal potential in terms of explaining pathogenesis and promoting the therapy of stress-sensitive cutaneous inflammation (Figure 1). However, its rank in the cascade of events following stress exposure is still unclear, and comparative analysis of the central, as well as the peripheral, stress response is urgently required.