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.

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.

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.

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.

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.

Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages.

To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1ß, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.

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.

Childhood Trauma and Psychosocial Stress Affect Treatment Outcome in Patients With Psoriasis Starting a New Treatment Episode.

Objective: Traumatic childhood experiences and psychosocial stress may predispose the evolvement of somatic diseases. Psoriasis is a multifactorial chronic inflammatory skin disease that often associates with current and past stress. Both may entail pathological alterations in major stress axes and a balance shift in the level of T helper type 1 (Th1) and 2 (Th2) cytokines, affecting the development and course of psoriasis. Until now, it is unclear whether traumatic stress experiences during the childhood or current stress are more frequent in psoriatic compared to skin-healthy individuals, and if they interact with treatment outcome. Method: In a prospective cohort study, the impact of acute and early childhood stress on the course of dermatological treatment were studied in patients with moderate to severe psoriasis (PSO). Patients were examined before (T1) and about 3 months after (T2) the beginning of a new treatment episode. Assessments included clinical outcomes (Psoriasis Area and Severity Index-PASI, Structured Clinical Interview SCID-I) and patient-reported outcomes (PRO) (Childhood Trauma Questionnaire-CTQ, Perceived Stress Scale-PSS, itching/scratching, Dermatology Life Quality Index-DLQI, Hospital Anxiety and Depression Scale, Body Surface Area, Self-Administered PASI). Results: N = 83 PSO patients (median age 53.7, IQR 37.8, 62.5) and n = 66 skin-healthy control subjects (HC) (median age 51.5, IQR 33.3, 59.2) participated. PSO had higher CTQ physical neglect than HC, as well as higher PRO levels. The positive impact of improved skin on the skin-related quality of life was moderated by the perceived stress. Acute stress at T1 had a positive effect both on the skin severity and the skin-related quality of life. CTQ total closely interacted with baseline psoriasis severity, and was associated with higher improvement from T1 to T2. Conclusion: One might tentatively conclude, that chronic psychosocial stressors like childhood maltreatment may predispose the manifestation of psoriasis. The latter may be amplified by acute psychological stressors. In addition, the present evidence suggests that systemic therapies work well in PSO, with childhood trauma and acute psychosocial stress. Both should therefore be routinely assessed and addressed in PSO.

[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.

S3 guideline Allergy Prevention.

BACKGROUND: The persistently high prevalence of allergic diseases in Western industrial nations and the limited possibilities of causal therapy make evidence-based recommendations for primary prevention necessary. METHODS: The recommendations of the S3 guideline Allergy Prevention, published in its last version in 2014, were revised and consulted on the basis of a current systematic literature search. The evidence search was conducted for the period 06/2013 - 11/2020 in the electronic databases Cochrane and MEDLINE, as well as in the reference lists of current reviews and through references from experts. The literature found was screened in two filtering processes, first by title and abstract, and the remaining papers were screened in the full text for relevance. The studies included after this were sorted by level of evidence, and the study quality was indicated in terms of potential bias (low/high). The revised recommendations were formally agreed and consented upon with the participation of representatives of the relevant professional societies and (self-help) organizations (nominal group process). Of 5,681 hits, 286 studies were included and assessed. RESULTS: Recommendations on maternal nutrition during pregnancy and breastfeeding as well as on infant nutrition in the first months of life again play an important role in the updated guideline: Many of the previous recommendations were confirmed by the current data. It was specified that breastfeeding should be exclusive for the first 4 - 6 months after birth, if possible, and that breastfeeding should continue with the introduction of complementary foods. A new recommendation is that supplementary feeding of cow's milk-based formula should be avoided in the first days of life if the mother wishes to breastfeed. Furthermore, it was determined that the evidence for a clear recommendation for hydrolyzed infant formula in non-breastfed infants at risk is currently no longer sufficient. It is therefore currently recommended to check whether an infant formula with proven efficacy in allergy prevention studies is available until the introduction of complementary feeding. Finally, based on the EAACI guideline, recommendations were made for the prevention of chicken egg allergy by introducing and regularly giving thoroughly heated (e.g., baked or hard-boiled) but not "raw" chicken egg (also no scrambled egg) with the complementary food. The recommendation to introduce peanut in complementary feeding was formulated cautiously for the German-speaking countries: In families who usually consume peanut, the regular administration of peanut-containing foods in age-appropriate form (e.g., peanut butter) with the complementary diet can be considered for the primary prevention of peanut allergy in infants with atopic dermatitis (AD). Before introduction, a clinically relevant peanut allergy must be ruled out, especially in infants with moderate to severe AD. There is still insufficient evidence for an allergy-preventive efficacy of prebiotics or probiotics, vitamin D, or other vitamins in the form of supplements so that recommendations against their supplementation were adopted for the first time in the current guideline. Biodiversity plays an important role in the development of immunological tolerance to environmental and food allergens: there is clear evidence that growing up on a farm is associated with a lower risk of developing asthma and allergic diseases. This is associated with early non-specific immune stimulation due to, among other things, the greater microbial biodiversity of house dust in this habitat. This aspect is also reflected in the recommendations on animal husbandry, on which a differentiated statement was made: In families without a recognizable increased allergy risk, pet keeping with cats or dogs should not generally be restricted. Families with an increased allergy risk or with children with already existing AD should not acquire a new cat - in contrast, however, dog ownership should not be discouraged. Interventions to reduce exposure to dust mite allergens in the home, such as the use of mite allergen-proof mattress covers ("encasings"), should be restricted to patients with already proven specific sensitization against house dust mite allergen. Children born by caesarean section have a slightly increased risk of asthma - this should be taken into account when advising on mode of delivery outside of emergency situations. Recent work also supports the recommendations on air pollutants: Active and passive exposure to tobacco smoke increase the risk of allergies, especially asthma, and should therefore be avoided. Exposure to nitrogen oxides, ozone, and small particles (PM 2.5) is associated with an increased risk, especially for asthma. Therefore, exposure to emissions of nitrogen oxides, ozone, and small particles (PM 2.5) should be kept low. The authors of this guideline are unanimously in favor of enacting appropriate regulations to minimize these air pollutants. There is no evidence that vaccinations increase the risk of allergies, but conversely there is evidence that vaccinations can reduce the risk of allergies. All children, including children at risk, should be vaccinated according to the current recommendations of the national public health institutes, also for reasons of allergy prevention. CONCLUSION: The consensus of recommendations in this guideline is based on an extensive evidence base. The update of the guideline enables evidence-based and up-to-date recommendations for the prevention of allergic diseases including asthma and atopic dermatitis.

Psychological Treatment Effects Unrelated to Hair-Cortisol and Hair-BDNF Levels in Chronic Tinnitus.

BACKGROUND: Currently, there are no objective markers to measure treatment efficacy in chronic (distressing) tinnitus. This study explores whether stress-related biomarkers cortisol and brain-derived neurotrophic factor (BDNF) measured in hair samples of chronic tinnitus patients change after compact multimodal tinnitus-specific cognitive behavioral therapy. METHODS: In this longitudinal study, hair-cortisol and hair-BDNF levels, self-reported tinnitus-related distress (Tinnitus Questionnaire; TQ), and perceived stress (Perceived Stress Questionnaire; PSQ-20) were assessed before and 3 months after 5 days of treatment in N = 80 chronic tinnitus patients. Linear mixed-effects models with backward elimination were used to assess treatment-induced changes, and a cross-lagged panel model (structural equation model) was used for additional exploratory analysis of the temporal associations between TQ and hair-BDNF. RESULTS: At follow-up, a reduction in TQ (p < 0.001) and PSQ-20 scores (p = 0.045) was observed, which was not influenced by baseline hair-cortisol or hair-BDNF levels. No changes in biomarker levels were observed after treatment. The exploratory analysis tentatively suggests that a directional effect of baseline TQ scores on hair-BDNF levels at follow-up (trend; p = 0.070) was more likely than the opposite directional effect of baseline hair-BDNF levels on TQ scores at follow-up (n.s.). DISCUSSION: While the treatment effectively reduced tinnitus-related distress and perceived stress in chronic tinnitus patients, this effect was not mirrored in biological changes. However, the lack of changes in hair-cortisol and hair-BDNF levels might have been influenced by the treatment duration, follow-up interval, or confounding medical factors, and therefore must be interpreted with caution. The relationship between tinnitus-related distress and hair-BDNF levels should be explored further to obtain a better understanding of stress-related effects in chronic tinnitus.

Hair-cortisol and hair-BDNF as biomarkers of tinnitus loudness and distress in chronic tinnitus.

The role of stress and its neuroendocrine mediators in tinnitus is unclear. In this study, we measure cortisol as an indicator of hypothalamus-pituitary-adrenal (HPA) axis alterations and brain-derived neurotrophic factor (BDNF) as a marker of adaptive neuroplasticity in hair of chronic tinnitus patients to investigate relationships with tinnitus-related and psychological factors. Cross-sectional data from chronic tinnitus inpatients were analyzed. Data collection included hair sampling, pure tone audiometry, tinnitus pitch and loudness matching, and psychometric questionnaires. Elastic net regressions with n-fold cross-validation were performed for cortisol (N = 91) and BDNF (N = 87). For hair-cortisol (R2 = 0.10), the strongest effects were sampling in autumn and body-mass index (BMI) (positive), followed by tinnitus loudness (positive) and smoking (negative). For hair-BDNF (R2 = 0.28), the strongest effects were hearing aid use, shift work (positive), and tinnitus loudness (negative), followed by smoking, tinnitus-related distress (Tinnitus Questionnaire), number of experienced traumatic events (negative), and physical health-related quality of life (Short Form-12 Health Survey) (positive). These findings suggest that in chronic tinnitus patients, higher perceived tinnitus loudness is associated with higher hair-cortisol and lower hair-BDNF, and higher tinnitus-related distress with lower hair-BDNF. Regarding hair-BDNF, traumatic experiences appear to have additional stress-related effects, whereas hearing aid use and high physical health-related quality of life appear beneficial. Implications include the potential use of hair-cortisol and hair-BDNF as biomarkers of tinnitus loudness or distress and the need for intensive future research into chronic stress-related HPA axis and neuroplasticity alterations in chronic tinnitus.

[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.

New Pathways for the Skin's Stress Response: The Cholinergic Neuropeptide SLURP-1 Can Activate Mast Cells and Alter Cytokine Production in Mice.

Background: The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown. Objective: To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits. Methods: Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1ß, IL10, TGFß, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice. Results: First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1ß+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1ß in cMC from Chrna7-KO and in IL1ß-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1ß in cMC when HIF1α was blocked. Conclusions: These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1ß expression if SLURP-1 is involved.

To stress or not to stress: Brain-behavior-immune interaction may weaken or promote the immune response to SARS-CoV-2.

The COVID-19 pandemic continues to strongly affect people with health disadvantages, creating a heavy burden on medical systems and societies worldwide. Research is growing rapidly and recently revealed that stress-related factors such as socio-economic status, may also play a pivotal role. However, stress research investigating the underlying psychoneuroimmune interactions is missing. Here we address the question whether stress-associated neuroendocrine-immune mechanisms can possibly contribute to an increase in SARS-CoV-2 infections and influence the course of COVID-19 disease. Additionally, we discuss that not all forms of stress (e.g. acute versus chronic) are detrimental and that some types of stress could attenuate infection-risk and -progression. The overall aim of this review is to motivate future research efforts to clarify whether psychosocial interventions have the potential to optimize neuroendocrine-immune responses against respiratory viral infections during and beyond the COVID-19 pandemic. The current state of research on different types of stress is summarized in a comprehensive narrative review to promote a psychoneuroimmune understanding of how stress and its mediators cortisol, (nor)adrenaline, neuropeptides and neurotrophins can shape the immune defense against viral diseases. Based on this understanding, we describe how people with high psychosocial stress can be identified, which behaviors and psychosocial interventions may contribute to optimal stress management, and how psychoneuroimmune knowledge can be used to improve adequate care for COVID-19 and other patients with viral infections.

Multimodal Psychotherapeutic Inpatient Therapy of Depression Is Successful in Patients With High Cytokine Production.

Objective: In experimental settings, systemically elevated inflammation markers interfere with major depression treatment. In German healthcare, compulsory national health insurance covers treatment of a wide variety of depressive disorders, if it follows evidence-based medicine guidelines combining recommended therapies. To date, little is known about the relevance of immune system cytokine production with regard to real-world clinical care for patients with moderate depression. Methods: Seventy three patients with moderate depression subjected to multimodal psychotherapeutic inpatient therapy (mPT) following a psychodynamic concept at a German university hospital were included. As a primary outcome, mPT success, evidenced by delta HADS "depression," was analyzed according to tumor necrosis factor alpha (TNFα) production by peripheral blood mononuclear cells (PBMC) after phytohemagglutinin (PHA) challenge at baseline. Secondary outcomes addressed the inflammatory response and mental health comparing high and low TNFα-producers. Results: First, higher PBMC TNFα production at baseline predicted a better mPT-outcome (R 2 0.162, p = 0.014). Second, patients with high TNFα (hTNF) at baseline produced significantly more acute inflammatory cytokines [interleukin (IL)1ß, IL6), TH1/TH2 cytokines [interferon gamma (IFNγ), IL4] as well as eotaxin and IL2 compared to low TNFα producers (lTNF) (Cohen's ds between -0.532 and -1.013). Demographic data, diagnosis subtype-distribution, medication, systemic inflammation markers [C-reactive protein (CRP), high mobility group box 1 (HMGB1), leptin], anxiety and depression (HADS) did not differ. From baseline to mPT-discharge, HADS "depression" decreased in both hTNF (11.31 to 5.47, p = 0.001, d = 1.184) and lTNF patients (11.50-7.92, p = 0.001, d = -0.765), while PBMC cytokine production decreased significantly in hTNF (Cohen's ds between -0.304 and -0.345) with a significant group by time interaction for TH1/TH2 ratio. At the end of therapy, comparison of TNF groups revealed significantly lower depression-scores in hTNF compared to lTNF patients (5.47 compared to 7.92, p = 0.035, d = 0.504). Conclusions: Our study demonstrates successful treatment of depression in a clinical care setting using multimodal psychotherapy based on a psychodynamic concept following guideline recommendation. The greatest improvement in patient depression was linked to the highest production of TNFα by PBMCs at baseline. Our study contributes to the definition of patient subpopulations with differing cytokine responses that are related to succesful treatment of depression.

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.