Regulation of cutaneous immunity by stress and the nervous system
Nerve-derived factors modulate immune and inflammatory mechanisms in the cutaneous system
It has long been believed that the nervous system and stress influence cutaneous immunity and inflammatory skin disorders. Stress is said to exacerbate skin diseases including psoriasis, atopic dermatitis, rosacea and acne, amongst others, and there is some evidence that stress alleviation improves psoriasis and atopic dermatitis. Also, stress is commonly believed to suppress immunity.
The observations that stress may exacerbate inflammatory skin disorders while suppressing immunity seem contradictory. Yet, recent work suggests mechanisms to explain such a possibility.
Langerhans Cells (LCs) and Neuropeptides (NP)
LCs are dendritic APCs residing in the epidermis. They classically have been believed to present antigen for initiation and expression of immune responses. A role for NPs in regulating LC function came from the observation that LCs are frequently anatomically associated with nerves containing calcitonin gene-related peptide (CGRP). CGRP is a neurotransmitter and potent vasodilator. Pre-treatment of LCs in vitro with CGRP inhibited their ability to present antigen to a T-T hybridoma, to Th1 clones and to present antigen for elicitation of delayed-type hypersensitivity (DTH) in previously immunized mice. CGRP inhibited upregulation of the co-stimulatory molecule CD86 and inhibited the stimulated expression of IL-1β and IL-12/23 p40 while upregulating expression of the Th1 suppressing cytokine interleukin (IL)-10, perhaps accounting for this effect. In contrast, CGRP exposure enhanced LC ability to present antigen for Th2-type responses. It also induced expression of Th2-type chemokines and inhibited the stimulated production of Th1-type chemokines, suggesting that CGRP modulates cutaneous immune responses by altering the T cell types recruited by LCs to sites of immune reactivity. One could speculate that exposure to CGRP from adjacent nerves may account, at least in part, for maintaining LCs in an immature state in which they are relatively inefficient in presenting antigen for Th1-type immune responses.
LCs express VPAC1 and VPAC2 receptors that respond to the NPs pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal polypeptide (VIP). These NPs also inhibit LC antigen presentation to Th1 clones and LC elicitation of DTH in previously sensitized mice. Interestingly, CGRP, PACAP and VIP all inhibit activation of the transcription factor NF-κB. The importance of the NFκB signaling pathway to antigen presentation is shown by the ability of a specific inhibitor of NFκB activation to profoundly inhibit LC antigen presenting capability for stimulation of a Th1 clone.
These immunosuppressive activities are not seen with all NPs. For example, substance P administered intradermally augments CHS.
Stressors induce a physiological response with autonomic nervous system activation and a sympathetico-adrenal response with release of adrenocorticotropic hormone, corticosteroids (CSs) and hypothalamic monoamines. Many animal studies show that acute stress can augment or suppress CHS responses. Interestingly, experiments with acute immobilization stressing of mice have been reported as producing both enhanced and suppressed responses, even when different investigators appeared to be following the same protocol with the same mouse strain. As the results may depend critically on duration and intensity of stress, it is most likely that small differences in technique accounted for these variations. This is in accordance with the finding that chronic stress always inhibits CHS in mice. Catecholamines and CSs contribute to both the enhancing and immunosuppressive effects of stress. In this regard, epinephrine (EPI) and norepinephrine (NE) inhibit the antigen presenting function of murine LCs via the β2-adrenergic receptor and similar effects have been reported with human bone marrow-derived DCs. There is evidence that NE can enhance immunity through effects on DC migration via the α1β-adrenergic receptor. Interestingly, intradermal administration of EPI results in inhibition of the induction of CHS by application of a hapten, not only at the injected site, but also at distant non-injected sites. It is not known whether this effect of epinephrine is due to alterations in APC function, trafficking of cells or other mechanisms.
With regard to cancer models, stressed mice show enhanced growth of a transplantable immunogenic tumor and mice exposed to UVR and stress develop more skin tumors than is induced by UVR alone.
Exacerbation of skin diseases by stress
Animal models support exacerbation of inflammatory skin disease by stress. Stressors can induce mast cell degranulation in mouse skin. NC/Nga mice develop a rash resembling atopic dermatitis when they are housed in standard conditions while in pathogen-free conditions they develop much less rash. When NC/Nga mice were stressed by placement on a plastic island in water, their rash worsened significantly, even when in a pathogen-free environment. Sound stress has been shown to increase allergen-induced dermatitis and there is evidence that substance P is an important mediator of this effect.
Our laboratory has recently performed studies suggesting another mechanism by which stress may increase skin inflammation, centered on the role of adenosine triphosphate (ATP) as a sympathetic co-transmitter. We hypothesized that under conditions of stress and activation of the sympathetic nervous system, ATP is released by sympathetic nerves at dermal blood vessels with pro-inflammatory effects. Both ATP and a long-lived hydrolysis-resistant analog, ATPγS, induced release of IL-6 and the chemokines CXCL1, CXCL8 and CCL2 from human dermal microvascular endothelial cells in vitro. ATPγS also upregulated expression of the adhesion molecule ICAM-1. These findings are consistent with a model in which release of ATP leads to changes favoring recruitment of leukocytes out of vessels and into the interstitium.
Much evidence supports the concept that nerve-derived factors modulate immune and inflammatory mechanisms within the skin and hypotheses regarding the mechanisms of stress-induced changes in cutaneous immunity and inflammation are being tested. A more complete understanding of these pathways may lead to novel approaches for the treatment of unwanted or inappropriate cutaneous immune reactivity.
Richard D. Granstein, M.D.
Chairman, Department of Dermatology
Weill Cornell Medical College
New York-Presbyterian Hospital
1305 York Avenue, 9th Floor
New York, NY 10021, USA