Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice

• Published in: Journal of investigative dermatology Vol. 128; no. 2; pp. 434 - 446
• Main Authors: Pavlovic, Sanja, Daniltchenko, Maria, Tobin, Desmond J., Hagen, Evelin, Hunt, Stephen P., Klapp, Burghard F., Arck, Petra C., Peters, Eva M.J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2008; Elsevier Limited
• Subjects: Animals; CD4 Lymphocyte Count; Cytokines - metabolism; Dermatitis, Atopic - immunology; Dermatitis, Atopic - physiopathology; Female; Mast Cells - immunology; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nerve Fibers - metabolism; Neurogenic Inflammation - immunology; Neurogenic Inflammation - physiopathology; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-1 - metabolism; Skin - immunology; Skin - innervation; Stress, Psychological - immunology; Stress, Psychological - physiopathology; Substance P - immunology; Substance P - metabolism; Th2 Cells - metabolism
• ISSN: 0022-202X; 1523-1747; 1523-1747
• DOI: 10.1038/sj.jid.5701079

A neurogenic component in atopy and allergy is evident and potentially of great pathogenic relevance. Stress was recently shown to activate elements of this component and is vividly discussed as a cause of exacerbation. However, to date, scientific proof of stress-induced neuronal plasticity and neuro-immune interaction in atopy or allergy remains lacking. Here we show early evidence that exposure to sound stress and atopic dermatitis-like allergic dermatitis (AD) equipotently raise the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P (SP) in mice. Stress increases AD readout parameters by at least 30% (eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, epidermal thickness). This dramatic pathologic exacerbation is associated with increased neurogenic inflammation (degranulated mast cells; interstitial neuropeptidergic dense core granules, mast cell apoptosis, endothelial gaping). Key features of AD exacerbation could not be induced in mice lacking the neurokinin-1 SP receptor (NK1). Interestingly, stress had no significant additional effect on CD4+ cell number, but shifted the cytokine profile toward TH2 in skin. Thus, we conclude that stress primarily exacerbates AD via SP-dependent cutaneous neurogenic inflammation and subsequent local cytokine shifting and should be considered as a therapeutic target, while it offers a convincing pathogenic explanation to affected patients and their frustrated physicians alike.