The “brain–skin connection”: nerve growth factor-dependent pathways for stress-induced skin disorders

Abstract

Keywords CNS.NGF.CRF.MastcellsStress can precipitate or exacerbate certain neuroinflamma-tory manifestations in peripheral tissues, including the skin.Indeed, stress may trigger or aggravate skin diseases, such asatopic dermatitis, psoriasis, urticaria, and alopecia areata ortotalis. The precise mechanisms leading to stress-induced or-aggravated skin disorders have just begun to be understood.Thus, recent experimental evidence reveals that distinctneuroendocrine pathways of the brain and the skin areintricately intertwined. This so-called “brain–skin connec-tion” represents an exciting new area of investigation [5].Mouse models are now available for the detailed mechanisticinvestigation of the effects of stress on skin diseases.The stress system in the brain and the periphery includesthe hypothalamic–pituitary–adrenal (HPA) axis and thearousal and sympathetic systems (Fig. 1). When activatedby stress, the stress system leads to several behavioral, neu-roendocrine,autonomic,andimmunechangesthatarepartofthe adaptive response [1]. Besides the classic stress-relatedneurohormones of the stress system [corticotropin-releasinghormone (CRH), arginine-vasopressin, adrenocorticotropichormone, glucocorticoids and the catecholamines norepi-nephrine and epinephrine], additional mediators, such asnerve growth factor (NGF) and several cytokines, havebeen identified as important players of the stress response.Circulating NGF levels are increased in patients withinflammatory skin diseases, such as psoriasis [7].Mast cells are involved in the development of allergicand late-phase inflammation reactions [2]. They are alsoimplicated in nonallergic inflammation, as they releaseseveral proinflammatory cytokines, such as tumor necrosisfactor and other inflammatory mediators (Table 1). Mastcells are located perivascularly in close proximity toperipheral neuron terminals, including both those ofpostganglionic sympathetic and sensory [dorsal root ganglia(DRG) neurons] neurons originating in the sympathetic andDRG, respectively (Fig. 1). Skin mast cells produce CRHand express CRH receptors type 1 [4, 6]. They can beactivated by many neuropeptides secreted by postganglion-ic sympathetic and sensory neurons, especially peripheralCRH, substance P (SP), and calcitonin gene-related peptide(CGRP), in response to stress, or by inflammatorymediators. Stress-induced or -aggravated neuroinflamma-tory skin conditions have been associated with mast cellactivation and degranulation. Similarly, we have previouslyshown that stress induces intracranial mast cell activation,through the sequential action of CRH and sensory neuro-peptides [9], and that CRH degranulates skin mast cells andincreases vascular permeability [8].In a murine model of stress involving exposure ofC57BL/6 mice to sound stress, Joachim et al. [3] in thisissue of the Journal provide evidence that stress, orintracutaneous injection of recombinant NGF mimickingthe skin’s response to stress, up-regulate the percentage ofSP