Stress Affects Mast Cell Proteases in Murine Skin in a Model of Atopic Dermatitis-like Allergic Inflammation.

Stress exposure worsens allergic inflammatory diseases substantially. Mast cells (MCs) play a key role in peripheral immune responses to neuroendocrine stress mediators such as nerve growth factor (NGF) and substance P (SP). Mast cell proteases (MCPs) and cholinergic factors (Chrna7, SLURP1) were recently described to modulate MC stress response. We studied MCPs and Chrna7/SLURP1 and their interplay in a mouse model for noise induced stress (NiS) and atopic dermatitis-like allergic inflammation (AlD) and in cultured MC lacking Chrna7. We found that the cholinergic stress axis interacts with neuroendocrine stress mediators and stress-mediator cleaving enzymes in AlD. SP-cleaving mMCP4+ MC were upregulated in AlD and further upregulated by stress in NiS+AlD. Anti-NGF neutralizing antibody treatment blocked the stress-induced upregulation in vivo, and mMCP4+ MCs correlated with measures of AlD disease activity. Finally, high mMCP4 production in response to SP depended on Chrna7/SLURP1 in cultured MCs. In conclusion, mMCP4 and its upstream regulation by Chrna7/SLURP1 are interesting novel targets for the treatment of allergic inflammation and its aggravation by stress.

Vitiligo - a disease: A position paper on stigmatization, life quality impairment and psychosocial comorbidity.

Vitiligo is a common disorder characterized by the visible loss of skin pigmentation. Non-segmental vitiligo (NSV) is the major subtype. The disease is caused by autoimmune-mediated destruction of melanocytes. Vitiligo leads to stigmatization and a significant reduction in quality of life. Disregarding the psychosocial burden, vitiligo is sometimes viewed solely as a cosmetic problem and, according to a global survey, is diagnosed on average only after 2.4 years. This delay contributes to a considerable burden of disease, including suicidal ideation. Stigmatization promotes the development of psychological comorbidities such as anxiety and depressive disorders, with prevalence rates varying by country and study (0.1%-67.9%). Data for Germany are heterogeneous and largely based on estimates. Due to psychosocial factors, the inflammatory component, and a higher incidence of somatic comorbidities, NSV may be regarded as an inflammatory systemic disease. We recommend optimizing care by incorporating the assessment of quality of life as a standard in routine care, in addition to monitoring disease activity. Moreover, early screening for psychological comorbidities is crucial to initiate appropriate treatment before the condition becomes chronic and cumulative (irreversible) impairments occur. The goal is a personalized and patient-centered integrated care approach that sustainably improves the health status of those affected.

The impact of perceived stress on the hair follicle: Towards solving a psychoneuroendocrine and neuroimmunological puzzle.

While popular belief harbors little doubt that perceived stress can cause hair loss and premature graying, the scientific evidence for this is arguably much thinner. Here, we investigate whether these phenomena are real, and show that the cyclic growth and pigmentation of the hair follicle (HF) provides a tractable model system for dissecting how perceived stress modulates aspects of human physiology. Local production of stress-associated neurohormones and neurotrophins coalesces with neurotransmitters and neuropeptides released from HF-associated sensory and autonomic nerve endings, forming a complex local stress-response system that regulates perifollicular neurogenic inflammation, interacts with the HF microbiome and controls mitochondrial function. This local system integrates into the central stress response systems, allowing the study of systemic stress responses affecting organ function by quantifying stress mediator content of hair. Focusing on selected mediators in this "brain-HF axis" under stress conditions, we distill general principles of HF dysfunction induced by perceived stress.

[Psychodermatology: Foundations for new developments in integrated care]. / Psychodermatologie: Grundlagen für den Aufbruch zu neuen Versorgungsformen.

The burden of a skin disease is easily understood by any observer due to its visibility: psychosocial issues are therefore ubiquitous in dermatology. Current evidence now shows that this relationship is two-way, as psychosocial stress can cause skin disease and its worsening. This interrelationship poses a major challenge.

[S1 Guideline Post-COVID/Long-COVID]. / S1-Leitlinie Post-COVID/Long-COVID.

The German Society of Pneumology initiated the AWMFS1 guideline Post-COVID/Long-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendation describes current post-COVID/long-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an expilcit practical claim and will be continuously developed and adapted by the author team based on the current increase in knowledge.

Effects of Early Life Stress on Bone Homeostasis in Mice and Humans.

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (µCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.

Diverse regulation of claudin-1 and claudin-4 in atopic dermatitis.

Tight junctions are important for skin barrier function. The tight junction protein claudin 1 (Cldn-1) has been reported to be down-regulated in nonlesional skin of atopic dermatitis (AD) patients. In contrast, we did not observe a significant down-regulation of Cldn-1 in nonlesional skin of the AD cohort used in this study. However, for the first time, a significant down-regulation of Cldn-1 in the upper and lower epidermal layers of lesional skin was detected. In addition, there was a significant up-regulation of Cldn-4 in nonlesional, but not lesional, AD skin. For occludin, no significant alterations were observed. In an AD-like allergic dermatitis mouse model, Cldn-1 down-regulation in eczema was significantly influenced by dermal inflammation, and significantly correlated with hallmarks of eczema (ie, increased keratinocyte proliferation, altered keratinocyte differentiation, increased epidermal thickness, and impaired barrier function). In human epidermal equivalents, the addition of IL-4, IL-13, and IL-31 resulted in a down-regulation of Cldn-1, and Cldn1 knockdown in keratinocytes resulted in abnormal differentiation. In summary, we provide the first evidence that Cldn-1 and Cldn-4 are differentially involved in AD pathogenesis. Our data suggest a role of Cldn-1 in AD eczema formation triggered by inflammation.

Comparison of patient-reported need of psycho-oncologic support and the doctor's perspective: how do they relate to disease severity in melanoma patients?

OBJECTIVE: Psycho-neuro-immune research suggests an association between cancer outcomes and psychosocial distress. Objective criteria to determine patients' levels of distress are important to establish potential links to disease outcomes. METHODS: We compared three patient-reported with one doctor-reported measures of psycho-oncologic distress frequently used in routine cancer care and investigated associations with standard disease severity parameters in melanoma patients. We enrolled n = 361 patients, successively seen at two outpatient university clinics in Germany. In the naturalistic study, n = 222 patients had been diagnosed <180 days and were seen for the first time (Group I); n = 139 had been diagnosed >180 days and were in after-care (Group II). RESULTS: Across groups, only moderate associations were seen between patient- reported and doctor-reported measures. Regarding clinical variables, disease severity and perceived need of psycho-oncologic support reported by patients or doctors showed hardly any association. After subgroup stratification, in patients of Group II, patient-reported and doctor-reported instruments showed some small associations with disease parameters commonly linked to more rapid cancer progression in patients who are in cancer after-care. CONCLUSIONS: Overall, the few and low associations suggest that need of psycho-oncologic support and clinical variables were largely independent of each other and doctors' perception may not reflect the patient's view. Therefore, the assessment of the patient perspective is indispensable to ensure that melanoma patients receive appropriate support, as such need cannot be derived from other disease parameters or proxy report. More research is needed applying psychometrically robust instruments that are ideally combined with sensitive biomarkers to disentangle psycho-neuro-immune implications in melanoma patients. Copyright © 2015 John Wiley & Sons, Ltd.

Stressed skin?--a molecular psychosomatic update on stress-causes and effects in dermatologic diseases.

A pathogenetically relevant link between stress, in terms of psychosocial stress, and disease was first described in the 1970s, when it was proven that viral diseases of mucous membranes (such as rhinovirus and Coxsackie virus infections) develop faster and more severe after stress exposure. Since then, there has been an annual increase in the number of publications which investigate this relationship and break it down to the molecular level. Nevertheless, the evidences for the impact of psychosocial stress on chronic inflammatory skin diseases and skin tumors are hardly known. In the present review, we outline current insights into epidemiology, psychoneuroimmunology, and molecular psychosomatics which demonstrate the manifold disease-relevant interactions between the endocrine, nervous, and immune systems. The focus is on stress-induced shifts in immune balance in exemplary disorders such as atopic dermatitis, psoriasis, and malignant melanoma. The objective of this article is to convey basic psychosomatic knowledge with respect to etiology, symptomatology, and therapeutic options for chronic skin diseases. Particular attention is directed towards the underlying molecular relationships, both from a somatic to mental as well as a mental to somatic perspective.

Balanced levels of nerve growth factor are required for normal pregnancy progression.

Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of the decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the establishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, in this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further boosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through recruitment of NGF-expressing immune cells, increased decidual innervation with substance P(+) nerve fibres and a Th1 cytokine shift. Similarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions associated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the models, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development. We further demonstrated that spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. Thus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed may result in fetal rejection due to exacerbated inflammation.

Psychosocial stress affects the change of mental distress under dermatological treatment-A prospective cohort study in patients with psoriasis.

Psoriasis is a chronic-inflammatory, immune-mediated disease leading to a state of increased systemic inflammation. Mental comorbidities often occur in the patients and may additionally affect the therapy outcome. Currently, it is unknown whether the disease severity, psychosocial stress or health-related quality of life determines the manifestation of anxiety/depression, or vice versa, in psoriasis. The interplay between these variables during the dermatological treatment of psoriasis remains to be elucidated in order to initiate appropriate psychological interventions and to identify patients at risk for comorbid anxiety/depression. In a prospective cohort study, the impact of disease severity, health-related quality of life and psychosocial stress on anxiety/depression were examined during the dermatological treatment in patients with moderate to severe psoriasis (patients with psoriasis = PSO). Patients were examined before (T1) and about 3 months after (T2) the beginning of a new treatment episode, in most cases by means of systemic therapy. Data were analysed, exploratory, using Bivariate Latent Change Score Models and mediator analyses. Assessments included patient-reported outcomes (Hospital Anxiety and Depression Scale/HADS, Perceived Stress Scale/PSS, Childhood Trauma Questionnaire/CTQ, Dermatology Life Quality Index-DLQI, Body Surface Area-BSA), at both T1 and T2. 83 PSO patients (37.3% women, median age 53.7, IQR 37.8-62.5, median BSA 18.0, IQR 9.0-40.0) with complete data of HADS and DLQI were included. In the total group, a higher anxiety/depression at T1 was associated with a lower improvement in psoriasis severity in the course of the dermatological treatment (γBSA  = 0.50, p < 0.001). In subgroups of PSO with low/high CTQ scores, anxiety/depression at T1 had no impact on the change in psoriasis severity. Only by tendency, in CTQ subgroups, a higher psoriasis severity at T1 was linked with a higher improvement in anxiety/depression at T2 (low/high CTQ, γHADS  = -0.16/-0.15, p = 0.08). An improvement in the health-related quality of life was positively associated with an improvement in anxiety/depression (Pearson's r = 0.49, p = 0.02). Here, the reduction of acute psychosocial stress seems to be a decisive factor, mediating this association (ß = 0.20, t [2,60] = 1.87; p = 0.07, 95% CI -0.01, 0.41). The results allude, that the initial severity of anxiety/depression may presumably have an impact on the treatment outcome in the total group. In contrast, analysing subgroups of patients with high/low childhood trauma, the impact of the initial disease severity on the course of anxiety/depression after a switch to a new dermatological treatment could not be conclusively ruled out. The latter results from the latent change score modelling should be treated cautiously because of the small sample size. A common aetiopathological mechanism for psoriasis and anxiety/depression might be assumed with impact of dermatological treatment on both. The change in perceived stress seems to play an important role in the manifestation of anxiety/depression, substantiating the need for adequate stress management in patients with increased psychosocial stress during their dermatological treatment.

Absence of IL-1ß positively affects neurological outcome, lesion development and axonal plasticity after spinal cord injury.

Precise crosstalk between the nervous and immune systems is important for neuroprotection and axon plasticity after injury. Recently, we demonstrated that IL-1ß acts as a potent inducer of neurite outgrowth from organotypic brain slices in vitro, suggesting a potential function of IL-1ß in axonal plasticity. Here, we have investigated the effects of IL-1ß on axon plasticity during glial scar formation and on functional recovery in a mouse model of spinal cord compression injury (SCI). We used an IL-1ß deficiency model (IL-1ßKO mice) and administered recombinant IL-1ß. In contrast to our hypothesis, the histological analysis revealed a significantly increased lesion width and a reduced number of corticospinal tract fibers caudal to the lesion center after local application of recombinant IL-1ß. Consistently, the treatment significantly worsened the neurological outcome after SCI in mice compared with PBS controls. In contrast, the absence of IL-1ß in IL-1ßKO mice significantly improved recovery from SCI compared with wildtype mice. Histological analysis revealed a smaller lesion size, reduced lesion width and greatly decreased astrogliosis in the white matter, while the number of corticospinal tract fibers increased significantly 5 mm caudal to the lesion in IL-1ßKO mice relative to controls. Our study for the first time characterizes the detrimental effects of IL-1ß not only on lesion development (in terms of size and glia activation), but also on the plasticity of central nervous system axons after injury.

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.

Hair cortisol as outcome parameter for psychological and neuropsychiatric interventions-a literature review.

Background: Studies measuring hair cortisol concentration (HCC) have been increasingly conducted to document stress-related, endocrine changes aggregated over time. Previous studies have shown that HCC reflects abnormalities in the hypothalamic-pituitary-adrenocortical axis (HPA axis) in the context of somatic diseases, such as Cushing's syndrome. HCC variations also reveal a corresponding alteration in HPA-axis-function in mental disorders, highlighting its potential role as a biomarker for interventions targeting mental health problems. Aims: The aim of this study was to investigate the role of HCC in various psychological and neuropsychiatric interventions and to explore the extent to which HCC can serve as a predictive or outcome parameter in such interventions by conducting a PRISMA-compliant review of the literature. Methods: From May to July 2022, the databases Web of Science, Google Scholar, PsychINFO, and ResearchGate were systematically searched using different combinations of relevant keywords. Studies of different types that examined HCC in the context of a wide range of psychological and neuropsychiatric interventions were included. Studies in languages other than English or German and animal studies were excluded. The MMAT tool was used, to assesses the Risk of bias. Results: The initial search identified 334 studies. After applying the inclusion and exclusion criteria, 14 publications with a total number of 1,916 participants were identified. An association between HCC and PTSD, depressive disorders, and ongoing social and family stress can be documented. The effect of relaxation techniques, mental training, CBT, or PTSD therapy on HCC has been studied with equivocal results. Some studies found decreased HCC after treatment, while others did not show a clear effect. Baseline HCC appears to be of particular importance. In some studies, higher baseline HCC was associated with increased treatment response, providing a predictive value for HCC. Discussion: HCC is increasingly being used as a biomarker for the mapping of psychological and neuropsychiatric interventions. However, due to the wide range of study populations and interventions, results are still heterogeneous. Nevertheless, HCC seems to be an encouraging biological parameter to describe the trajectory of different interventions aimed at improving mental health.

Study protocol: Neuro-inflammatory parameters as mediators of the relationship between social anxiety and itch intensity: A cross-sectional, controlled laboratory study in patients with psoriasis and healthy skin controls.

INTRODUCTION: Psoriasis (PSO) is a disease that in the majority of patients is accompanied by itch, which imposes a great burden and positively relates to anxiety. Social anxiety, a facet of anxiety associated with social withdrawal, may be a predictor of itch intensity in this patient group. Moreover, anxiety is linked to the secretion of neuroendocrine and inflammatory parameters such as substance P (SP), interleukin (IL)-6 and IL-17, which are also related to itch. In this research project, we investigate first, whether there is a direct relationship between social anxiety and itch intensity in patients with PSO and second whether the secretion of SP, IL-6 and IL-17 in the skin mediates this relationship. Additionally, PSO-patients are compared to healthy skin controls regarding their level of social anxiety, itch intensity and the secretion of SP, IL-6 and IL-17. METHODS AND ANALYSES: For study 1, we aim to recruit 250 psoriasis patients and 250 healthy skin controls who complete questionnaires to assess social anxiety, itch intensity and control variables (e.g. sociodemographic variables and severity of PSO). A linear hierarchic regression will be used to determine whether social anxiety significantly contributes to itch intensity. In study 2, we plan to apply the suction blister method to 128 patients and healthy skin controls recruited from study 1 to determine SP, IL-6 and IL-17 in tissue fluid extracted from the skin. A mediation analysis will be conducted using the SPSS-macro PROCESS to test whether the relationship between social anxiety and itch is mediated by SP, IL-6 and IL-17. TRIAL REGISTRATION NUMBERS: DRKS00023621 (study 1) and DRKS00023622 (study 2).

Hair brain-derived neurotrophic factor (BDNF) as predictor of developing psychopathological symptoms in childhood.

BACKGROUND: Dysregulation in the expression of neurotrophins is implicated in the pathophysiology of several mental disorders. Peripheral brain-derived neurotrophic factor (BDNF) can be measured in hair and might represent a marker of adequate neuroplasticity regulation. In early developmental periods, neuroplasticity regulation might be particularly important, but BDNF markers have not yet been analyzed in this regard. We used the hair-BDNF concentration (HBC) to investigate the prediction of emerging symptoms of anxiety/depressive and attention-deficit hyperactivity disorder (ADHD) in the developmentally crucial period from preschool to school age. METHODS: 117 children (58 girls, 59 boys) participated in a longitudinal study at the ages of 4-5 (T1) and 8 (T2) years. At T1, HBC was measured in a 3 cm hair segment. At T1 and T2, symptom domains were assessed using a multi-method (clinical interview, questionnaire) and multi-informant approach. RESULTS: T1 HBC was significantly negatively associated with T1 anxiety/depressive symptoms (r = -0.27) and predicted T2 anxiety disorder symptoms (r = -0.34) after controlling for the T1 symptoms. T1 HBC also predicted T2 depressive disorder symptoms (r = -0.18) but was not associated with ADHD symptom development. LIMITATIONS: BDNF hair analysis is a new method with a not yet large number of studies on methodological issues. Our study adds evidence to the validity of the method. CONCLUSIONS: Prediction of anxiety/depressive symptom development by HBC was shown. As this study was the first to use HBC in this context, cross-validation is necessary and worthwhile. HBC might prove to constitute a useful, non-invasive early marker of risk for anxiety/depressive disorders in childhood.

Perspectives of (/memorandum for) systems thinking on COVID-19 pandemic and pathology.

Is data-driven analysis sufficient for understanding the COVID-19 pandemic and for justifying public health regulations? In this paper, we argue that such analysis is insufficient. Rather what is needed is the identification and implementation of over-arching hypothesis-related and/or theory-based rationales to conduct effective SARS-CoV2/COVID-19 (Corona) research. To that end, we analyse and compare several published recommendations for conceptual and methodological frameworks in medical research (e.g., public health, preventive medicine and health promotion) to current research approaches in medical Corona research. Although there were several efforts published in the literature to develop integrative conceptual frameworks before the COVID-19 pandemic, such as social ecology for public health issues and systems thinking in health care, only a few attempts to utilize these concepts can be found in medical Corona research. For this reason, we propose nested and integrative systemic modelling approaches to understand Corona pandemic and Corona pathology. We conclude that institutional efforts for knowledge integration and systemic thinking, but also for integrated science, are urgently needed to avoid or mitigate future pandemics and to resolve infection pathology.

Oxidative stress coping capacity (OSC) value: Development and validation of an in vitro measurement method for blood plasma using electron paramagnetic resonance spectroscopy (EPR) and vitamin C.

Oxidative stress as a driver of disease is reinforcing the trend towards supplementation with antioxidants. While antioxidants positively influence the redox status when applied at physiological doses, higher concentrations may have pro-oxidative effects. Precise assessment methods for testing the supply of antioxidants are lacking. Using in-situ-irradiation as stressor and electron paramagnetic resonance (EPR) spectroscopy as readout system for formed radicals, a stress response assessment method was developed, using protein solutions and plasma samples from transfusion medicine. The method was validated in a double-blind placebo-controlled in vivo cross-over pilot study in blood plasma samples of individuals before and after vitamin C supplementation. Reference measurements were performed for the exogenous antioxidants ß-carotene and vitamin C, and glutathione as an endogenous representative. Malondialdehyde was studied for oxidative stress indication. Protein solutions without antioxidants showed a linear increase in radical concentration during irradiation. The in-vitro-addition of vitamin C or plasma samples from subjects displayed two slopes (m1, m2) for radical production, whereby m1 represented the amount of antioxidants and proteins, m2 only the protein content. These two slopes in combination with the intervening transition area (T) were used to calculate the oxidative stress coping capacity (OSC), which correlated positively with vitamin C concentration in blood plasma, while oxidative stress biomarkers showed only fluctuations within their reference ranges. Furthermore, a selective radical quenching mechanism for vitamin C was observed: the proportion of reactive oxygen species (ROS) in the plasma samples was degraded in dependence to the vitamin C concentration ingested. The proportion of lipid oxygen species (LOS) remained stable while the ascorbyl radical increased with higher vitamin C intake. OSC may represent a sensitive method to detect treatment effects on the redox status in vivo in future validation and treatment studies, and potentially in clinical routine.