Christiane Liezmann

Substance P Is a Key Mediator of Stress-Induced Protection from Allergic Sensitization via Modified Antigen Presentation

Interaction between the nervous and immune systems greatly contributes to inflammatory disease. In organs at the interface between our body and the environment, the sensory neuropeptide substance P (SP) is one key mediator of an acute local stress response through neurogenic inflammation but may also alter cytokine balance and dendritic cell (DC) function. Using a combined murine allergic inflammation/noise stress model with C57BL/6 mice, we show in this paper that SP—released during repeated stress exposure—has the capacity to markedly attenuate inflammation. In particular, repeated stress exposure prior to allergen sensitization increases DC-nerve fiber contacts, enhances DC migration and maturation, alters cytokine balance, and increases levels of IL-2 and T regulatory cell numbers in local lymph nodes and inflamed tissue in a neurokinin 1-SP-receptor (neurokinin-1 receptor)-dependent manner. Concordantly, allergic inflammation is significantly reduced after repeated stress exposure. We conclude that SP/repeated stress prior to immune activation acts protolerogenically and thereby beneficially in inflammation.

Stress, atopy and allergy A re-evaluation from a psychoneuroimmunologic persepective

Since the early days of psychosomatic thinking, atopic disease was considered exemplary. In the 70s and 80s numerous reports stated increased anxiety, depression or ill stress-coping in atopics in correlation with enhanced disease activity. Employed patient groups however were small and diverse and controls rare. Therefore, the question remained, whether psychopathological findings in atopics were of pathogenetic relevance or an epiphenomenon of chronic inflammatory disease. Recently, the discussion has been revived and refocused by psychoneuroimmunological findings. We now know that atopic disease is characterized by an imbalance of the classical stress-axis response along the hypothalamus-pituitary-adrenal axis (HPA) and the sympathetic axis (SA). This imbalance can be found shoulder to shoulder with enhanced expression of newly emerging neuroendocrine stress mediators such as substance P (SP) and nerve growth factor that form up to a third stress axis (neurotrophin neuropeptide axis: NNA). Together they can alter the inflammatory as well as the neuroendocrine stress-response on several levels. In skin, the immediate inflammatory response to stress involves neuropeptide release and mast cell degranulation, in short neurogenic inflammation. Systemically, antigen-presentation and TH2 cytokine bias are promoted under the influence of cortisol and neuropeptides. Imbalanced stress-responsiveness may therefore be at the core of exacerbated allergic disease and deserves re-evaluation of therapeutic options such as neutralisation of SP-signalling by antagonists against its receptor NK1, cortisol treatment as supplementation and relaxation techniques to balance the stress-response.

Nerve Growth Factor Partially Recovers Inflamed Skin from Stress-Induced Worsening in Allergic Inflammation

Neuroimmune dysregulation characterizes atopic disease, but its nature and clinical impact remain ill-defined. Induced by stress, the neurotrophin nerve growth factor (NGF) may worsen cutaneous inflammation. We therefore studied the role of NGF in the cutaneous stress response in a mouse model for atopic dermatitis-like allergic dermatitis (AlD). Combining several methods, we found that stress increased cutaneous but not serum or hypothalamic NGF in telogen mice. Microarray analysis showed increased mRNAs of inflammatory and growth factors associated with NGF in the skin. In stress-worsened AlD, NGF-neutralizing antibodies markedly reduced epidermal thickening together with NGF, neurotrophin receptor (tyrosine kinase A and p75 neurotrophin receptor), and transforming growth factor-β expression by keratinocytes but did not alter transepidermal water loss. Moreover, NGF expression by mast cells was reduced; this corresponded to reduced cutaneous tumor necrosis factor-α (TNF-α) mRNA levels but not to changes in mast cell degranulation or in the T helper type 1 (Th1)/Th2 cytokine balance. Also, eosinophils expressed TNF receptor type 2, and we observed reduced eosinophil infiltration after treatment with NGF-neutralizing antibodies. We thus conclude that NGF acts as a local stress mediator in perceived stress and allergy and that increased NGF message contributes to worsening of cutaneous inflammation mainly by enhancing epidermal hyperplasia, pro-allergic cytokine induction, and allergy-characteristic cellular infiltration.

Skin and hair follicle innervation in experimental models: a guide for the exact and reproducible evaluation of neuronal plasticity

Abstract:  The remodelling of skin innervation is an instructive example of neuronal plasticity in the peripheral nervous system. Cutaneous innervation displays dramatic plasticity during morphogenesis, adult remodelling, skin diseases and after skin nerve lesions. To recognize even subtle changes or abnormalities of cutaneous innervation under different experimental conditions, it is critically important to use a quantitative approach. Here, we introduce a simple, fast and reproducible quantitative method based on immunofluorescence histochemistry for the exact quantification of peripheral nerve fibres. Computer‐generated schematic representations of cutaneous innervation in defined skin compartments are presented with the aim of standardizing reports on gene and protein expression patterns. This guide should become a useful tool when screening new mouse mutants, disease models affecting innervation or mice treated with pharmaceuticals for discrete morphologic abnormalities of skin innervation in a highly reproducible and quantifiable manner. Moreover, this method can be easily transferred to other densely innervated peripheral organs.

Profiling mRNA of the Graying Human Hair Follicle Constitutes a Promising State-of-the-Art Tool to Assess Its Aging: An Exemplary Report

Determining hitherto uninvestigated and safe targets to halt the aging process is important in our aging society. Graying is a hallmark of the aging process and may be used to identify aging tissue for comparative analysis. Here we analyzed differential gene expressions between pigmented, gray, and white human scalp skin hair follicles (HFs) from identical donors. Forming intersections between five donors identified 194/192 downregulated and 186/177 upregulated genes in gray/white HFs. These included melanogenesis (tyrosinase; tyrosinase-related protein 1)- and melanosome structure (Melan-A; Pmel17)-associated genes and regulation of melanocyte relevant tyrosine kinases. Alongside these expected changes, regulated genes included nonmelanocyte-related genes associated with aging as well as nonaging-related genes associated with melanocytes. Intriguingly, among them, genes associated with energy metabolism (i.e., glutaminase) and axon guidance (plexin C1) were altered. These results were reflected by pathway analysis and exemplarily confirmed by PCR and immunohistochemical studies. Supplementing cultured HFs with glutamine or plexin C1 revealed biological relevance and pharmacointerventional potential of these microarray results in altering the HF aging process. Together, we present intriguing data obtained from intra-individual sample comparison that suggest the graying HF to be a valid aging model and a promising target for testing therapeutic interventions.

Analyzing the microarray mRNA profile of graying human hair follicles: a promising approach in stress and aging research

Regenerative medicine needs new but safe treatment approaches to balance the reported increase in stress and aging related diseases. Graying is one hallmark of aging and is associated with excessive oxidative as well as psycho-emotional stress. In graying individuals fully pigmented hair follicles are found next to white and intermediary hair follicles. Thus, young and old hair follicles are observed in parallel that share the identical genetic background. Here, we discuss data obtained by microarray analysis of 15 tissue samples, and we studied the functional relevance in the ex vivo hair follicle organ culture model. We found the expected regulation of genes responsible for pigment-production by melanocytes, the cells that generate the pigment and are gradually lost from graying hair follicles. Among the around 200 regulated gens, we also found genes associated with cellular energy metabolism (e.g. glutaminase) and with nerve fiber growth (e.g. plexin C1). These results could be confirmed on mRNA and protein level as well as by pathway-analysis. Ex vivo treatment of cultured hair follicles with l -glutamine or plexin C1 revealed biological relevance and pharmaco-interventional potential of these selected microarray-results in that these compounds were able to halt the culture-induced premature aging process and cellular stress responses (pigment production, cell proliferation, -differentiation, -apoptosis, senescence). We therefore consider the graying hair follicle a useful model to study aging and stress associated responses and report here energy metabolism and cellular plasticity as important areas for future research.

Is TH17 immunity altered by chronically perceived stress

Inflammatory injury requires tissue regeneration, a process hampered by chronic stress exposure in many experimental settings. The reported shift of the immune balance towards adaptive humoral immunity reported in chronically stressed mice and man may be the functional link. We here report results obtained in females exposed to exam stress. In these individuals subjective perception of anxiety (state and trait anxiety index – STAI) as well as a nervous mood (multidimensional mood questionnaire – MDMQ) prominently characterized chronic stress perception throughout a twelve week examination preparation and execution period. During the same time period exam participants displayed reduced morning serum cortisol levels prior to exam (exam preparation) and during exam execution when compared to expression levels in participants not exposed to exam stress. They also showed significantly increased serum level of the neurotrophin brain derived neurotrophic factor (BDNF). Correspondingly, the summary score for cytokines conducting the TH17 response differed significantly between exam participants and controls during exam preparation. These results link decreased hypothalamus pituitary adrenal axis function during chronic stress exposure with increased neurotrophin expression and TH17 dominated immunity. Future research will determine relevance for chronic inflammatory diseases driven by respective immune-dysfunction.

Neurogenic control of the cutaneous stress response: A yin and yang example for neuro-immune interaction

314 Effects of the chronic treatment of 5-HT4 receptor agonist (RS 67333) in subjects with different coping in response to social stress E. Gómez-Lázaro, A. Arregi, G. Beitia, O. Vegas, A. Azpiroz, L. Garmendia Department of Basic Psychological Processes and their Development, Avda, Tolosa 70, Basque Country University, San Sebastián, Guipuzcoa

24. A new role for the spleen as a conductor of neuro-immune regulation in allergic dermatitis?

these cytotoxic effector lymphocytes easily attached to activated endothelium and this effect was reversed by epinephrine. In contrast naive, central memory and effector memory CD4+ and CD8+ T-cells declined 3 h after cortisol administration, correlated negatively with endogenous cortisol levels and were characterized by high expression of CXCR4. In vitro these T-cell subsets showed further upregulation of CXCR4 expression by cortisol. Epinephrine sensitive lymphocytes did not respond to cortisol, and cortisol sensitive lymphocytes did not so to epinephrine. CX3CR1 and CXCR4 expression was highly correlated to epinephrine and cortisol sensitivity as well as to circadian daytime increases and decreases, respectively. Thus, activation of the two major stress axes via the release of epinephrine and cortisol induces a unique redistribution of lymphocyte subsets with different functions: Epinephrine releases lymphocytes with cytotoxic effector potential from the marginal pool most likely via an attenuation of CX3CR1/CD11a signaling. On the other hand, cortisol redirects T-cells without immediate effector potential to the sheltering bone marrow most likely via CXCR4 upregulation. This compartmentalization might reflect a basic adaptation during stress to allow for acute defense of invading pathogens, whereas adaptive immune responses that are in need of costimulation and evolve more slowly are diminished.