Depression is one of the global leading causes of disability, but treatments remain limited and classical antidepressants were found to be ineffective in a substantial proportion of patients. Thus, ...novel effective therapies for the treatment of depression are urgently needed. Given the emerging role of inflammation in the etiology and pathophysiology of affective disorders, we herein illustrate how experimental endotoxemia, a translational model of systemic inflammation, could be used as a tool to develop and test new therapeutic options against depression. Our concept is based on the striking overlap of inflammatory, neural, and affective characteristics in patients with inflammation-associated depression and in endotoxin-challenged healthy subjects. Experimental administration of endotoxin in healthy volunteers is safe, well-tolerated, and without known long-term health risks. It offers a highly standardized translational approach to characterize potential targets of therapies against inflammation-associated depression, as well as to identify characteristics of patients that would benefit from these interventions, and, therefore, could contribute to improve personalization of treatment and to increase the overall rate of responders.
•We have compared inflammation-induced sickness behavior in rodents and humans.•LPS-induced signs of sickness in rodents and humans appear to follow similar patterns.•Depressive- and anxiety-like ...behaviors cannot be compared in a straightforward manner between rodents and humans.•Subjective and objective measurements of sickness behavior in humans are needed.
Increasing evidence from animal and human studies suggests that inflammation may be involved in mood disorders. Sickness behavior and emotional changes induced by experimental inflammatory stimuli have been extensively studied in humans and rodents to better understand the mechanisms underlying inflammation-driven mood alterations. However, research in animals and humans have remained compartmentalized and a comprehensive comparison of inflammation-induced sickness and depressive-like behavior between rodents and humans is lacking. Thus, here, we highlight similarities and differences in the effects of bacterial lipopolysaccharide administration on the physiological (fever and cytokines), behavioral and emotional components of the sickness response in rodents and humans, and discuss the translational challenges involved. We also emphasize the differences between observable sickness behavior and subjective sickness reports, and advocate for the need to obtain both subjective reports and objective measurements of sickness behavior in humans. We aim to provide complementary insights for translational clinical and experimental research on inflammation-induced behavioral and emotional changes, and their relevance for mood disorders such as depression.
Highlight • This review summarizes studies employing administration of endotoxin as a model to analyze neuropsychological consequences of systemic inflammation in humans.
In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, ...due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas’ grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.
Graphical abstract
Highlights • Maternal poly(I:C) challenge induces presynaptic hippocampal deficits in adult offspring. • Prenatal immune activation leads to postsynaptic hippocampal deficits in pubescence. • ...Hippocampal IL-1β is increased in adulthood without signs of systemic inflammation. • Synaptic deficits occur in absence of microglial anomalies.
Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative ...impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits.
Inflammation, both acute and chronic, is associated with testosterone deficiency, raising the possibility of a direct causal link. One potential trigger for inflammation in obese men is the passage ...of intestinal bacteria into the circulation due to a breakdown in mucosal barrier integrity. Recently, we hypothesized that this endotoxin exposure may cause androgen deficiency in obese men. To test this hypothesis, we analyzed the relationship between serum levels of lipopolysaccharide-binding protein (LBP), an indirect measure of endotoxin exposure, against male reproductive hormones, inflammatory markers (C-reactive protein, IL-1β, IL-6, TNF-α), and adiposity in 75 men. Adiposity was positively correlated with endotoxin exposure (LBP) and inflammation (C-reactive protein, IL-6) and negatively correlated with testosterone. Furthermore, endotoxemia (LBP) was negatively correlated with serum testosterone but positively correlated with IL-6. Multivariate analysis revealed a significant, negative correlation between serum IL-6 and free testosterone. In a second interventional study, low-dose endotoxin challenge in lean men produced a transient inflammatory response that was followed by a decline in serum testosterone, without changes in LH or FSH, providing further evidence that endotoxin-driven inflammation may result in impaired Leydig cell function.
Common Fundamentals of Psoriasis and Depression Hölsken, Stefanie; Krefting, Frederik; Schedlowski, Manfred ...
Acta dermato-venereologica,
11/2021, Letnik:
101, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Psoriasis is an inflammatory, immune-mediated disease that is frequently associated with psychological comorbidities such as depression. The stigma patients feel because of the appearance of their ...skin may contribute to the high psycho-social burden of psoriasis. However, there is emerging evidence that overlapping biological mechanisms are, to a substantial degree, responsible for the close interaction between psoriasis and depression. Increased proinflammatory mediators, such as C-reactive protein or interleukin-6, are present in both psoriasis and depression, indicating that inflammation may represent a pathophysiological link between the diseases. Anti-inflammatory biologic therapies treat the clinical manifestations of psoriasis, but might also play a significant role in reducing associated depressive symptoms in patients with psoriasis. Comparison between single studies focusing on the change in depressive symptoms in psoriasis is limited by inconsistency in the depression screening tools applied.
Fumaric acid esters (FAEs) remain a widespread therapy option for moderate-to-severe psoriasis. However, drug survival of FAEs is limited by adverse events (AEs) or inadequate treatment response. ...Depressive disturbances are highly prevalent in psoriasis patients and are hypothesized to be associated with the reporting of AEs and therapy discontinuation. This study's aim was to analyze whether psoriasis patients with comorbid depressive symptomatology are more likely to discontinue treatment with FAEs due to AEs and/or inadequate treatment response. Data were retrospectively extracted from the records of patients starting therapy with FAEs in the Department of Dermatology, University Hospital Essen, Germany between 2017 and 2022, covering the first 52 weeks of treatment. Psoriasis severity and depressive symptomatology, as well as AEs and therapy discontinuation, were analyzed. Psoriasis patients (N = 95, 47.37% female) with depressive symptomatology (42.11%) were more likely to discontinue therapy due to patient-reported AEs, while the total number of reported AEs was not associated with depression. The results support the hypothesis that among psoriasis patients with depressive symptoms, the associated introspection and somatization may result in increased sensitivity for AEs and thus in quicker therapy discontinuation. In these patients, the occurrence of nocebo effects should be minimized, e.g. by special communication techniques.
Abstract For many years, anecdotal evidence and clinical observations have suggested that exposure to psychosocial stress can affect disease outcomes in immune-related disorders such as viral ...infections, chronic autoimmune diseases and tumors. Experimental evidence in humans supporting these observations was, however, lacking. Studies published in the last 2 decades in Brain, Behavior and Immunity and other journals have demonstrated that acute and chronic psychological stress can induce pronounced changes in innate and adaptive immune responses and that these changes are predominantly mediated via neuroendocrine mediators from the hypothalamic–pituitary–adrenal axis and the sympathetic–adrenal axis. In addition, psychological stress has predicted disease outcomes using sophisticated models such as viral challenge, response to vaccination, tracking of herpesvirus latency, exploration of tumor metastasis and healing of experimental wounds, as well as epidemiological investigations of disease progression and mortality. These studies have contributed significantly to our understanding that the neuroendocrine–immune interaction is disturbed in many pathophysiological conditions, that stress can contribute to this disturbance, and that malfunction in these communication pathways can play a significant role in the progression of disease processes. There are, however, significant gaps in the extant literature. In the coming decade(s), it will be essential to further analyze neuroendocrine–immune communication during disease states and to define the specific pathways linking the central nervous system to the molecular events that control important disease-relevant processes. This knowledge will provide the basis for new therapeutic pharmacological and non-pharmacological behavioral approaches to the treatment of chronic diseases via specific modulation of nervous system–immune system communication.
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