Neuroimmunology of stress: skin takes center stage

Abstract

Like few other organs, the skin is continuously exposed to multiple exogenous and endogenous stressors. Superimposed on this is the impact of psychological stress on skin physiology and pathology. Here, we review the "brain-skin connection," which may underlie inflammatory skin diseases triggered or aggravated by stress, and we summarize relevant general principles of skin neuroimmunology and neuroendocrinology. Specifically, we portray the skin and its appendages as both a prominent target of key stress mediators (such as corticotropin-releasing hormone, ACTH, cortisol, catecholamines, prolactin, substance P, and nerve growth factor) and a potent source of these prototypic, immunomodulatory mediators of the stress responses. We delineate current views on the role of mast cell-dependent neurogenic skin inflammation and discuss the available evidence that the skin has established a fully functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis as an independent, local stress response system. To cope with stress-induced oxidative damage, the skin and hair follicles also express melatonin, probably the most potent neuroendocrine antioxidant. Lastly, we outline major, as-yet unmet challenges in cutaneous stress research, particularly in the study of the cross-talk between peripheral and systemic responses to psychological stress and in the identification of promising molecular targets for therapeutic stress intervention.

Figure 1. Brain–skin cross-talk upon exposure to psychological stress or environmental stress factors

Upon perception of psychological stress, the central stress response leads to the activation of the hypothalamic–pituitary–adrenal axis, which causes the release of corticotropin-releasing hormone (CRH), ACTH, and prolactin (PRL). Further, an upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) can be observed in the dorsal root ganglia. Such stress response patterns may be translated into a skin stress response, including the local production of CRH, ACTH, and glucocorticoids (GCs), the release of inflammatory cytokines, and the sprouting of SP⁺ nerve fibers. In the skin response to stress, mast cells occupy a central switchboard position, as they are targets for stress-triggered factors as well as effector cells that contribute, for example, to neurogenic inflammation in the skin. Environmental factors are also capable of inducing a skin stress response, and this may be signaled to the brain, where it affects behavior and leads to an increased vulnerability to additional stress perception. NGF, nerve growth factor.

Figure 2. Stress mediators and effector cells in the neuro-endocrine-immune environment of the skin

Activated mast cells may skew the immune response toward the selective suppression of an adaptive T helper 1 (Th1) response and encourage a shift to a Th2 bias, promoting humoral immunity via IL-4. On the other hand, mast-cell activation may lead to neurogenic inflammation of the skin and promote cellular immunity, accompanied by sprouting of substance P (SP)-positive nerve fibers, endothelial-cell activation, vascular leakage, and angiogenesis. Via the release of tryptase by mast cells, proteinase-activated receptors (PARs) are activated, which additionally enhance neurogenic inflammation and vascular leakage. Further, the capability of releasing corticotropin-releasing hormone (CRH) and the presence of CRH receptor (CRH-R) allow mast cells to contribute to the activation of the skin hypothalamic–pituitary–adrenal (HPA) axis. APC, antigen-presenting cell.

Figure 3. Mast cells: important regulators of neurogenic inflammation during stress responses

A multitude of mediators, the majority of which are released upon stress challenge, act as mast-cell activators. The activation subsequently results in the synthesis or the release of pre-stored mediators, which may then trigger a wealth of dermatological diseases. CGRP, calcitonin gene-related peptide; CRH, corticotropin-releasing hormone; cysLTs, cysteinyl leukotrienes; NGF, nerve growth factor; PACAP, pituitary adenylate cyclase-activating polypeptide; PGD2, prostaglandin D2; SCF, stem cell factor; SP, substance P; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; Ucn, urocortin; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide.