Brain-Thymus Connections in Chagas Disease.

BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.

Does dehydroepiandrosterone sulfate have a role in COVID-19 prognosis and treatment?

The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory conditions and modulated immunological response. Limited evidence is available regarding the incidence and the effect of HPA dysfunction in COVID-19. Although the cortisol levels have only been estimated in a few studies, the dehydroepiandrosterone sulfate (DHEAS) release from the adrenal gland has not been explored yet. In this mini review, the authors discuss the role of dehydroepiandrosterone (DHEA) and DHEAS in the acute stress response and immunological modulation. Various effects of DHEAS have been demonstrated in different diseases. The specific inhibitory effect of DHEA on interleukin 6 (IL-6) could be of paramount importance in COVID-19. Further, DHEA supplementation has already been proposed in inflammatory conditions, like rheumatoid arthritis. DHEAS levels in COVID-19 may help to understand the HPA axis dysfunction as well as the possibility of repurposing DHEA as a drug for mitigating the pro-inflammatory COVID-19.

Enhancing Effects of Environmental Enrichment on the Functions of Natural Killer Cells in Mice.

The environment of an organism can convey a powerful influence over its biology. Environmental enrichment (EE), as a eustress model, has been used extensively in neuroscience to study neurogenesis and brain plasticity. EE has also been used as an intervention for the treatment and prevention of neurological and psychiatric disorders with limited clinical application. By contrast, the effects of EE on the immune system are relatively less investigated. Recently, accumulating evidence has demonstrated that EE can robustly impact immune function. In this review, we summarize the major components of EE, the impact of EE on natural killer (NK) cells, EE's immunoprotective roles in cancer, and the underlying mechanisms of EE-induced NK cell regulation. Moreover, we discuss opportunities for translational application based on insights from animal research of EE-induced NK cell regulation.

Impacts of Immunometabolism on Male Reproduction.

The physiological process of male reproduction relies on the orchestration of neuroendocrine, immune, and energy metabolism. Spermatogenesis is controlled by the hypothalamic-pituitary-testicular (HPT) axis, which modulates the production of gonadal steroid hormones in the testes. The immune cells and cytokines in testes provide a protective microenvironment for the development and maturation of germ cells. The metabolic cellular responses and processes in testes provide energy production and biosynthetic precursors to regulate germ cell development and control testicular immunity and inflammation. The metabolism of immune cells is crucial for both inflammatory and anti-inflammatory responses, which supposes to affect the spermatogenesis in testes. In this review, the role of immunometabolism in male reproduction will be highlighted. Obesity, metabolic dysfunction, such as type 2 diabetes mellitus, are well documented to impact male fertility; thus, their impacts on the immune cells distributed in testes will also be discussed. Finally, the potential significance of the medicine targeting the specific metabolic intermediates or immune metabolism checkpoints to improve male reproduction will also be reassessed.

Loss of vagal integrity disrupts immune components of the microbiota-gut-brain axis and inhibits the effect of Lactobacillus rhamnosus on behavior and the corticosterone stress response.

The vagus nerve is one of the major signalling components between the gut microbiota and brain. However, the exact relationship between gut-brain signaling along the vagus and the effects of gut microbes on brain function and behaviour is unclear. In particular, the relationship between the vagus nerve and immune signaling, that also appears to play a critical role in microbiota-gut-brain communication, has not been delineated. The aim of the present study was to determine the effect of subdiaphragmatic vagotomy on peripheral and central immune changes associated with the anxiolytic actions of L.rhamnosus. Male mice underwent vagotomy or sham surgery, followed by administration of L.rhamnosus for 14 days. L.rhamnosus administration following sham surgery resulted in reduced anxiety-like behaviour, and an attenuation of the hypothalamic-pituitary-adrenal axis (HPA axis), as indicated by reduced plasma corticosterone after acute restraint stress. These effects were associated with an increase in splenic T regulatory cells and a decrease in activated microglia in the hippocampus. The anxiolytic effects, HPA modulation and increase in T regulatory cells were prevented by vagotomy, whereas vagotomy alone led to a significant increase in activated microglia in the hippocampus that was not altered with L.rhamnosus treatment. Thus, both microbe induced and constitutive vagal signaling influences critical immune components of the microbiota-gut-brain axis. These findings suggest that, rather than acting as a direct neural link to the central nervous system, the role of the vagus nerve in gut-microbe to brain signalling is as an integral component of a bi-directional neuroimmunoendocrine pathway.

Interdisciplinary approaches are fundamental to decode the biology of adversity.

The COVID-19 pandemic has highlighted structural inequalities and racism promoting health disparities among communities of color. Taking cardiovascular disease as an example, we provide a framework for multidisciplinary efforts leveraging translational and epidemiologic approaches to decode the biological impacts of inequalities and racism and develop targeted interventions that promote health equity.

Altered immunoemotional regulatory system in COVID-19: From the origins to opportunities.

The emergence of the novel coronavirus (SARS-CoV-2) and the worldwide spread of the coronavirus disease (COVID-19) have led to social regulations that caused substantial changes in manners of daily life. The subsequent loneliness and concerns of the pandemic during social distancing, quarantine, and lockdown are psychosocial stressors that negatively affect the immune system. These effects occur through mechanisms controlled by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenocortical (HPA) axis that alter immune regulation, namely the conserved transcriptional response to adversity (CTRA), which promotes inflammation and diminishes antiviral responses, leading to inadequate protection against viral disease. Unhealthy eating habits, physical inactivity, sleep disturbances, and mental health consequences of COVID-19 add on to the pathological effects of loneliness, making immunity against this ferocious virus an even tougher fight. Therefore, social isolation, with its unintended consequences, has inherently paradoxical effects on immunity in relation to viral disease. Though this paradox can present a challenge, its acknowledgment can serve as an opportunity to address the associated issues and find ways to mitigate the adverse effects. In this review, we aim to explore, in detail, the pathological effects of the new social norms on immunity and present suggested methods to improve our physical, psychological, and healthcare abilities to fight viral infection in the context of the COVID-19 pandemic.

Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression.

In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.

Cytokine Storm in COVID19: A Neural Hypothesis.

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.

Peripubertal stress following maternal immune activation sex-dependently alters depression-like behaviors in offspring.

There is an increasing evidence that maternal immune activation can render the offspring more vulnerable to the impacts of peripubertal stress on behavioral abnormalities in adulthood. The aim of this study was to investigate the combined effects of maternal immune activation and peripubertal stress on depression-related behaviors in male and female offspring. Pregnant mice were treated with lipopolysaccharides (LPS) or vehicle, and then offspring were subjected to stressful conditions or left unstressed during peripubertal period. Four behavioral tests including novelty-suppressed feeding test, sucrose preference test, tail suspension test, and forced swim test were used to measure depression-related behaviors in offspring. The activity of hypothalamic-pituitary-adrenal (HPA) or - gonadal (HPG) axes were also evaluated by measuring basal and stress-induced corticosterone, testosterone and estradiol levels in the serum of offspring. Our findings revealed that mild maternal immune activation and peripubertal stress interacted synergistically to induce depression-related symptoms and HPA axis hyperactivity in male offspring, whereas no significant changes were observed in female offspring. We also found that this combination of environmental factors significantly decreased serum testosterone and estradiol levels in adult male and female offspring respectively. There were also significant correlations between behavioral parameters and hormones. Taken together, these findings show that the combination of two environmental risk factors can predispose the male offspring to increased depression-related symptoms in adulthood as compared to the females. This study suggests that the combination of maternal immune activation and peripubertal stress can alter depression-related behaviors and HPA axis function in a sex-dependent manner.

Effects of alkylphenols mixture on the adrenal gland of the lizard Podarcis sicula.

Alkylphenols (AP) are widespread environmental compounds belonging to the large family of substances known as Endocrine Disrupting Chemicals (EDCs). The present study was carried out to assess the effects of Octylphenol (OP) alone and in combination with Nonylphenol (NP) on the hypothalamus-pituitary-adrenal gland (HPA) axis of the lizard Podarcis sicula. Lizards are good bioindicators due to their features such as wide distribution, large population and good sensitivity to contaminants. Results obtained showed a time and dose-dependent stimulation of the HPA together with a high variation of both catecholamine plasma levels and greater vascularization and hypertrophy of steroidogenic cord of adrenal gland after both OP and OP + NP treatments. Interestingly, the OP + NP mixture treatment has provoked a state of stress of the adrenal gland which in fact appeared to be characterized by the presence of a marked macrophage infiltration which can be seen especially close to the connective capsule surrounding the gland. This macrophage infiltration could be an evidence of a particularly pronounced inflammatory state to indicate, probably, an animal's response to a non-physiological situation.

Immune-toxicity effects of scorpion venom on the hypothalamic pituitary adrenal axis during rest and activity phases in a rodent model.

Scorpion venom is a complex mixture of peptides and proteins, rich in toxins. Its toxicological effects are related to central disruptions and autonomic disturbances, organ failure, as well as an excessive systemic inflammatory response. Since the role of the hypothalamic pituitary adrenal (HPA) axis is central in the neuroendocrine-immunological axis, the purpose of this study was, therefore, to examine the immunotoxic effect of Androctonus australis hector (Aah) venom on HPA-axis in synchronised-mice model. Taking into account the circadian activity of the HPA-axis, the variations of adrenocorticotropic hormone and corticosterone plasma levels, oxidative stress as well as inflammatory markers in cerebral, hypothalamic and adrenal tissue homogenates were investigated during the rest and activity phases of animals. Histopathology study was also performed. Results showed that Aah venom activated the HPA axis. This response seems to be dependent on time of envenomation, as a higher hormone levels were more operative during the active phase than in the rest phase when compared to time-matched control. The local toxicity-effects following Aah envenomation revealed an imbalance in oxidative stress with a higher antioxidant defences in darkness hypothalamic and cerebral tissues. Furthermore, there were significantly higher levels in vascular permeability in hypothalamic and cerebral tissues accompanied by a concomitant increase in immune-cell infiltration and/or activation as shown by expression of CD68 and myeloperoxidase activity during the active phase compared with the rest phase. Overall results suggested that Aah venom had a toxic impact on different HPA-axis areas and the effect varies according to the time of envenomation.

Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: insights from computational model for circadian-neuroendocrine-immune interactions.

Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC50-dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F (NR3C1-1F), IC50-DEX, and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

Neuroinflammation and depressive disorder: The role of the hypothalamus.

Data accumulated over the last two decades has demonstrated that hypothalamic inflammation plays an important role in the etiopathogenesis of the most prevalent diseases, such as cardiovascular diseases, metabolic syndrome, and even cancer. Recent findings indicate that hypothalamic inflammation is also associated with stress exposure and certain psychiatric diseases, such as depressive disorder. Mechanistic studies have shown that intense and/or chronic stress exposure is accompanied by the synthesis of inflammatory molecules in the hypothalamus, altered hypothalamic-pituitary-adrenal axis activity, and development of glucocorticoid resistance. Consequently, these factors might play a role in the etiopathogenesis of psychiatric disorders. We propose that hypothalamic inflammation represents an interconnection between somatic diseases and depressive disorder. These assumptions are discussed in this mini-review in the light of available data from studies focusing on hypothalamic inflammation.

Remitted depression and cognition in HIV: The role of cortisol and inflammation.

In major depressive disorder (MDD) and remitted MDD (rMDD) alterations in cortisol and inflammation are associated with cognitive difficulties, but these relationships have not been investigated in HIV. We used secondary data from a placebo-controlled, cross-over study of cognitive performance following a probe of the hypothalamic-pituitary-adrenal (HPA) axis (low dose hydrocortisone; LDH 10 mg) in 65 people with HIV (PWH; 36 women). Using placebo data, we examined sex-specific associations between two biomarkers - basal afternoon salivary cortisol and salivary inflammatory cytokines - cognition, and rMDD. Salivary cortisol and inflammatory biomarkers were sampled across the 5 -h study. The panel of inflammatory markers included interleukin (IL)-6, IL-8, IL-1ß, tumor necrosis factor-(TNF)-α, CRP, interferon gamma-induced protein (IP-10), monocyte chemotactic protein (MCP)-1, monokine induced by interferon (MIG), matrix metalloproteinase MMP-9, and MMP-1. Learning, memory, attention/concentration, and executive function were assessed 30 min and 4 h after the placebo intervention; visuospatial ability was also assessed 30 min after the placebo intervention. For women but not men with HIV, basal cortisol concentrations were higher in rMDD versus noMDD groups, and related to poorer learning and memory. For men and women with HIV, basal inflammatory cytokines were higher in rMDD versus noMDD groups, but were negatively related to cognition independent of rMDD status. Cortisol and cytokines relate to cognition in PWH, but the associations depended on sex, rMDD status, and their interaction.

Antidepressant-like effects of penta-acetyl geniposide in chronic unpredictable mild stress-induced depression rat model: Involvement of inhibiting neuroinflammation in prefrontal cortex and regulating hypothalamic-pituitaryadrenal axis.

We previously reported that penta-acetyl geniposide ((Ac)5GP, an acetylated derivative of geniposide) exhibited better pharmacological functions than geniposide, a major active component of Gardenia jasminoides Ellis. This study demonstrated the antidepressant-like effects of (Ac)5GP and its involved mechanisms using a rat depression model caused by chronic unpredictable mild stress (CUMS). Behavioral tests including sucrose preference, open field and forced swimming were applied to evaluate depression symptoms. IL-1ß, IL-6 and TNF-α mRNA and protein levels in prefrontal cortex (PFC) were respectively measured by quantitative PCR and ELISA. The protein levels of IκBα, p-IκBα, NF-κB p65, NLRP3, pro- and mature-IL-1ß in PFC were determined by western blot. The activity of hypothalamic-pituitaryadrenal (HPA) axis was also measured. (Ac)5GP treatment alleviated the CUMS-induced depressive-like behaviors in rats, as indicated by increased sucrose intake, increased total crossing and rearing numbers, improved central activity and reduced immobility time. (Ac)5GP reversed the CUMS-induced elevations of IL-1ß, IL-6 and TNF-α mRNA and protein levels in PFC. (Ac)5GP reduced degradation and phosphorylation of IκBα and protein level of nuclear NF-κB p65 in PFC. (Ac)5GP also decreased the mRNA and protein levels of NLRP3 and reduced the ratio of mature-IL-1ß protein over total IL-1ß protein (pro-IL-1ß + mature-IL-1ß) in PFC. Moreover, (Ac)5GP reduced serum levels of adrenocorticotropic hormone/corticosterone and mRNA level of hypothalamic corticotrophin-releasing hormone. In conclusion, (Ac)5GP treatment improved the depressive-like behaviors in CUMS rats perhaps by suppressing neuroinflammation in PFC and inhibiting activations of NF-κB and NLRP3 and also attenuating HPA axis hyperactivity.

Does exposure to parasites modify relationships between diurnal cortisol and leukocytes among Honduran women?

BACKGROUND: Altered hypothalamic-pituitary-adrenal (HPA) function and related changes in circulating glucocorticoids have been implicated in the pathogenesis of numerous diseases that involve dysregulated immune function. Glucocorticoid hormones have both direct and indirect modulatory effects on both pro- and anti-inflammatory aspects of the immune system, including granulocytic and lymphocytic leukocyte subsets. However, past findings are complicated by inconsistencies across studies in how glucocorticoids and immune markers interact and relate to disease risk. Some incongruencies are likely due to an overreliance on single-unit (e.g., HPA or one immune marker) measures, and a failure to consider ecological exposures that may shape the base levels or correspondence between these systems. Here, we test single-unit and diurnal measures of HPA axis and immune system interactions in a less-industrial ecological setting with relatively high parasite loads. METHODS: In a sample of 114 Honduran women (mean age = 36 years), morning and evening blood samples were analyzed to quantify granulocytes, lymphocytes, and immunoglobulin-E (IgE). Saliva was collected over 2 days (8 samples per woman) to measure peak cortisol, cumulative cortisol, and slope of decline. These repeated measures of saliva and venous blood were used to investigate associations between single-point and diurnal salivary cortisol and leukocytes, under variable levels of past parasite exposure (proxied by IgE). RESULTS: Individuals with less of a decline in cortisol (i.e., "flatter" decline) show less of an increase in lymphocytes (2.27% increase in cells/µL/hr; 95% CI: 0.91-7.29; p = .01) across the day compared to those with steeper cortisol decline (7.5% increase in lymphocytes; 95% CI: 5.79-9.34; p < .001). IgE levels did not modify this association. Interestingly, IgE did moderate relationships between measures of cortisol and granulocytes: diurnal cortisol was positively associated with granulocytes, only in individuals with high previous exposure to parasites. There were no consistent relationships between single-unit measures of cortisol, lymphocytes or granulocytes, regardless of past parasite exposure. DISCUSSION: Results demonstrate that the relationship between HPA function and immune modulation cannot be fully understood without an understanding of local disease ecology. These results highlight the importance of research that seeks to identify etiologies of disease across environmental contexts.

Gut Microbiota: A Perspective for Psychiatrists.

There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.

Critical Roles of Endogenous Glucocorticoids for Disease Tolerance in Malaria.

During malaria, the hypothalamic-pituitary-adrenal (HPA) axis is activated and glucocorticoid (GC) levels are increased, but their essential roles have been largely overlooked. GCs are decisive for systemic regulation of vital processes such as immune responses, vascular function, and metabolism, which are crucial in malaria. Here, we introduce GCs in general, followed by their versatile roles for disease tolerance in malaria. A complementary comparison is provided with their role in sepsis. Finally, potential translational implications are considered. The failed clinical trials of dexamethasone against cerebral malaria in the past have diminished the interest in GCs in malaria. However, the issue of relative corticosteroid insufficiency has barely been explored in malaria patients, but may hold promise for a better understanding and treatment of specific malaria complications.