Cocaine-use disorder and childhood maltreatment are associated with the activation of neutrophils and increased inflammation.

BACKGROUND: Cocaine-use disorder (CUD) has been associated with early life adversity and activated cellular immune responses. Women are most vulnerable to complications from chronic substance disorders, generally presenting an intense feeling of abstinence and consuming significant drug amounts. Here, we investigated neutrophil functional activities in CUD, including the formation of neutrophil extracellular traps (NETs) and related intracellular signalling. We also investigated the role of early life stress in inflammatory profiles. METHODS: Blood samples, clinical data, and history of childhood abuse or neglect were collected at the onset of detoxification treatment of 41 female individuals with CUD and 31 healthy controls (HCs). Plasma cytokines, neutrophil phagocytosis, NETs, intracellular reactive oxygen species (ROS) generation, and phosphorylated protein kinase B (Akt) and mitogen-activated protein kinases (MAPK)s were assessed by flow cytometry. RESULTS: CUD subjects had higher scores of childhood trauma than controls. Increased plasma cytokines (TNF-α, IL-1ß, IL-6, IL-8, IL-12, and IL-10), neutrophil phagocytosis, and production of NETs were reported in CUD subjects as compared to HC. Neutrophils of CUD subjects also produced high levels of intracellular ROS and had more activated Akt and MAPKs (p38/ERK), which are essential signalling pathways involved in cell survival and NETs production. Childhood trauma scores were significantly associated with neutrophil activation and peripheral inflammation. CONCLUSION: Our study reinforces that smoked cocaine and early life stress activate neutrophils in an inflammatory environment.

Severe psychiatric disorders and general medical comorbidities: inflammation-related mechanisms and therapeutic opportunities.

Individuals with severe psychiatric disorders, such as mood disorders and schizophrenia, are at increased risk of developing other medical conditions, especially cardiovascular and metabolic diseases. These medical conditions are underdiagnosed and undertreated in these patients contributing to their increased morbidity and mortality. The basis for this increased comorbidity is not well understood, possibly reflecting shared risks factors (e.g. lifestyle risk factors), shared biological mechanisms and/or reciprocal interactions. Among overlapping pathophysiological mechanisms, inflammation and related factors, such as dysbiosis and insulin resistance, stand out. Besides underlying the association between psychiatric disorders and cardiometabolic diseases, these mechanisms provide several potential therapeutic targets.

Neuroinflammation in Mood Disorders: Role of Regulatory Immune Cells.

Mood disorders are associated with chronic low-grade systemic (sterile) inflammation, with increased plasma levels of pro-inflammatory mediators targeting all tissues including the brain. Importantly, pro-inflammatory cytokines (ex., tumor-necrosis factor alpha [TNF-α], interleukin [IL]-6) regulate mood behavior and cognition by influencing neurotransmitter levels, activating stress-responsive endocrine axes, among other effects. However, the mechanisms underlying this enhanced inflammation are not well understood. There is increasing evidence indicating that impaired immunoregulatory mechanisms may play a role in this context. Patients with mood disorders (major depression [MDD] and bipolar disorder [BD]) have reduced numbers of major regulatory cells of both innate (natural killer regulatory cells and myeloid-derived suppressor cells [MDSCs]) and adaptive immune responses (CD4+CD25+FoxP3+, B regulatory cells). Dysfunctional regulatory immune cells might contribute to systemic and neuroinflammation observed in mood disorders via different mechanisms, such as: (i) failure to develop adequate stress-related responses, (ii) indirectly through microglial activation, (iii) lack of trophic support and pro-cognitive functions of T cells in the brain, and (iv) dysbiosis. In conclusion, maladaptive immunoregulatory mechanisms seem to be involved with both onset and progression of mood disorders. A deeper understanding of these mechanisms may lead to the development of new therapeutic strategies.

Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression.

Patients with rheumatoid arthritis (RA) develop features of accelerated ageing, including immunosenescence. These changes include decreased thymic functionality, expansion of late-differentiated effector T cells, increased telomeric attrition, and excessive production of cytokines (senescence-associated secretory phenotype). The progression of RA has been associated with the early development of age-related co-morbidities, including osteoporosis, cardiovascular complications, and cognitive impairment. Here I review data supporting the hypothesis that immune-senescence contributes to the aggravation of both articular and extra-articular manifestations. Of note, poor cognitive functions in RA were associated with senescent CD28- T cells, inflammaging, and autoantibodies against brain antigens. The pathways of immune-to-brain communication are discussed and provide the rationale for the cognitive impairment reported in RA.

Decreased percentage of CD4+ lymphocytes expressing chemokine receptors in bipolar disorder.

OBJECTIVE: Although accumulating evidence supports the hypothesis that immune/inflammatory mechanisms are associated with the pathophysiology of bipolar disorder (BD), data about the profile of chemokines (chemotactic cytokines) and chemokine receptors are still scarce. The current study was designed to evaluate the expression of chemokine receptors on lymphocytes of patients with BD in comparison with controls. METHODS: Thirty-three patients with type I BD (N = 21 in euthymia; N = 6 in mania/hypomania; N = 6 in depression) and 22 age- and sex-matched controls were subjected to clinical evaluation and peripheral blood draw. The expression of chemokine receptors CCR3, CCR5, CXCR4, and CXCR3 on CD4+ and CD8+ lymphocytes was assessed by flow cytometry. RESULTS: Patients with BD had decreased percentage of CD4+CXCR3+ (p = 0.024), CD4+CCR3+ (p = 0.042), and CD4+CCR5+ (0.013) lymphocytes in comparison with controls. The percentage of both CD4+ and CD8+ lymphocytes expressing the chemokine receptor CXCR4 was similar in patients with BD and controls. Likewise, the percentages of CD8+CXCR3+, CD8+CCR3+, and CD8+CCR5+ lymphocytes were similar in patients with BD and controls. CONCLUSION: Our findings reinforce the hypothesis that immune pathways, especially involving CD4+ lymphocytes, are involved in the physiopathology of BD.

High Volume Exercise Training in Older Athletes Influences Inflammatory and Redox Responses to Acute Exercise.

To examine whether the volume of previous exercise training in older athletes influences inflammatory, redox, and hormonal profiles, 40 trained marathon runners were divided into higher-volume (HVG, ∼480 min/week) and lower-volume groups (LVG, ∼240 min/week). Plasma inflammatory proteins, redox biomarkers, salivary testosterone, and cortisol were assessed at restand following two maximal acute exercise bouts. At rest, the LVG exhibited higher CRP, higher protein carbonyls, and lower SOD activity compared to the HVG (p's < .05). In response to exercise, TNF-α declined similarly in both groups whereas CRP increased differentially (+60% LVG; +24% HVG; p's < .05). Protein carbonyls decreased and thiols increased similarly in both groups, but SOD declined differentially between groups (-14% LVG; -20% HVG; p's < .05). Salivary testosterone decreased similarly in both groups, whereas cortisol did not change. A higher volume of training is associated with favorable inflammatory and redox profiles at rest, perhaps mediated by small inflammatory responses to acute exercise.

HLA-G and CD8+ regulatory T cells in the inflammatory environment of pre-eclampsia.

During pregnancy, the maternal immune system is tolerant to foetal antigens via the engagement of immune regulatory mechanisms. Failure in regulating the maternal immunity to foetal antigens may lead to pre-eclampsia (PE). We addressed the role of HLA-G gene polymorphisms and protein expression as well as regulatory T cells and Th1/Th2/Th17 cytokines in healthy and pathological pregnancies. Blood samples from 26 pregnant women with PE, 25 non-PE and 7 strictly healthy pregnant women were assessed. PBMCs were phenotyped for early activation markers (CD25 and CD69), regulatory T-cell markers (CD8+CD28- and CD4+CD25highFoxp3+), ILT-2 (HLA-G receptor) and HLA-G. Lymphocyte proliferation was estimated and levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α and IL-17 were measured. HLA-G polymorphisms (rs66554220 and rs1063320) were genotyped by PCR. PE women exhibited low levels of HLA-G in PBMCs and low frequency of regulatory CD8+CD28- T cells. High amounts of the pro-inflammatory cytokines IL-17, IL-2 and TNF-α as well as IL-4 and IL-10 and an increased proliferative cell activation profile were observed in PE. The allelic and genotypic frequencies of the HLA-G gene polymorphisms and the frequency of CD4+CD25highFoxp3+ T cells did not vary among the groups. Our data suggest that the cytokine imbalance presented in PE is associated with a deficient immune regulatory profile, contributing to an impaired immune tolerance between mother and foetus.

Peripheral leukocyte profile in people with temporal lobe epilepsy reflects the associated proinflammatory state.

INTRODUCTION: Markers of low-grade peripheral inflammation have been reported amongst people with epilepsy. The mechanisms underlying this phenomenon are unknown. We attempted to characterize peripheral immune cells and their activation status in people with temporal lobe epilepsy (TLE) and healthy controls. METHODS AND RESULTS: Twenty people with TLE and 19 controls were recruited, and peripheral blood lymphocyte and monocyte subsets evaluated ex vivo by multi-color flow cytometry. People with TLE had higher expression of HLA-DR, CD69, CTLA-4, CD25, IL-23R, IFN-γ, TNF and IL-17 in CD4(+) lymphocytes than controls. Granzyme A, CTLA-4, IL-23R and IL-17 expression was also elevated in CD8(+) T cells from people with TLE. Frequency of HLA-DR in CD19(+) B cells and regulatory T cells CD4(+)CD25(+)Foxp3(+) producing IL-10 was higher in TLE when compared with controls. A negative correlation between CD4(+) expressing co-stimulatory molecules (CD69, CD25 and CTLA-4) with age at onset of seizures was found. The frequency of CD4(+)CD25(+)Foxp3(+) cells was also positively correlated with age at onset of seizures. CONCLUSION: Immune cells of people with TLE show an activation profile, mainly in effector T cells, in line with the low-grade peripheral inflammation.

Neuroimmunoendocrine interactions in post-traumatic stress disorder: focus on long-term implications of childhood maltreatment.

Childhood maltreatment has been linked to enhanced vulnerability to psychiatric pathologies in adult life, including post-traumatic stress disorder (PTSD). Previous works have reported cogent neuroendocrine and immune changes related to adult traumatic events (war survivors, refugees, etc.), but little information is known regarding the impact of early-life stress (ELS) in adult physiology. Here, we review the neuroendocrine and immunological changes commonly observed in PTSD, focusing on the long-term implications of ELS. Childhood maltreatment may lead to altered glucocorticoid (GC) secretion, resulting in hypo- or hypercortisolemia, and reciprocal changes in peripheral leukocyte sensitivity to GC. It is believed that these neuroendocrine changes are correlated with the immune imbalance phenomenon (low-grade inflammation), characterized by increased plasma levels of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) and C-reactive protein. Changes in peripheral lymphocyte subsets are also documented, such as a reduction in regulatory T cells and an expansion of activated T cells. The excess of circulating cytokines may thus interfere with key brain neurotransmitter pathways involved in depression and enhanced risk to cardiovascular, respiratory, gastrointestinal, inflammatory and autoimmune diseases. Recent gene-environment and epigenetic findings have indicated potential molecular mechanisms linking ELS, neuroendocrine and immunity in PTSD.

Psychoneuroendocrine interventions aimed at attenuating immunosenescence: a review.

There is evidence suggesting that immunosenescence can be accelerated by external factors such as chronic stress. Here we review potential psychoneuroendocrine determinants of premature aging of the immune system and discuss available interventions aimed at attenuating immunosenescence. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis. The immunological impact of such neuroendocrine dysregulation may be further amplified by a dramatic decline in dehydroepiandrosterone (DHEA) levels, acting in part as an endogenous glucocorticoid antagonist. Stress-buffering strategies show beneficial effects on various biomarkers in elderly populations. Likewise, supplementation of DHEA, melatonin or growth hormone has yielded significant beneficial effects in a number of studies, including: increased well-being, memory performance, bone mineral density and improved immunocompetence as evidenced by results of in vitro (T cell proliferation, cytotoxicity, cytokine production), and in vivo immune challenges. However, the side-effects of hormonal supplementation are also discussed. Finally, moderate exercise via the promotion of cortisol/DHEA balance or epigenetic modifications, is associated with lower serum pro-inflammatory cytokines, greater lymphoproliferative responses and lower counts of senescent T cells. Taken together, these data suggest that immune system is plastic and immunosenescence can be attenuated psychoneuroendocrine interventions.

Neuroimmunoendocrine interactions in patients with recurrent major depression, increased early life stress and long-standing posttraumatic stress disorder symptoms.

BACKGROUND: Traumatic events experienced in childhood may lead to psychiatric diseases in adult life, including major depressive disorder (MDD). It remains obscure to what extent early life stress (ELS) is associated with biologically relevant changes in MDD. OBJECTIVE: We investigated both neuroendocrine and immunological correlates in recurrent MDD with ELS and current posttraumatic stress disorder symptoms. METHODS: Thirty-eight female MDD patients with or without childhood trauma and 15 healthy controls took part in this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed by radioimmunoassays. Peripheral blood mononuclear cells (PBMCs) were isolated and T cell proliferation and cellular sensitivity to steroids and DHEAS were evaluated by colorimetric assays. Th1/Th2 cytokines were assessed by cytometric bead arrays. RESULTS: MDD patients with or without previous trauma had similarly lower salivary cortisol and DHEAS in parallel with blunted T cell proliferation. PBMCs of depressives were significantly less sensitive to dexamethasone or epinephrine than those of the controls. PBMCs of MDD patients produced significantly lower interleukin (IL)-2, IL-4 and tumor necrosis factor-α levels when compared to healthy controls. CONCLUSION: We found that a history of ELS did not modify the blunted neuroendocrine and immunological alterations presented by recurrent depressed patients.

Peripheral glucocorticoid sensitivity in children with controlled persistent asthma.

BACKGROUND: Persistent asthma in children is a chronic inflammatory disease and glucocorticoids (GCs) are currently recognized as the mainstay of therapy. Clinical and in vitro steroid resistance has been demonstrated in severe asthma. However, GC insensitivity has not been studied in children with controlled persistent asthma. OBJECTIVES: To analyze peripheral blood mononuclear cell (PBMC) sensitivity to GC in children (6-15 years) with persistent asthma and healthy controls. METHODS: Children with persistent asthma were selected and lung function and skin-prick tests were performed in all studied asthmatic children. PBMCs were isolated and cultured in vitro to assess mitogen-induced proliferation and cellular sensitivity to dexamethasone. RESULTS: Fifty-seven children with persistent and controlled asthma (mean age 10 years) were recruited and divided into 3 groups (severe, moderate and mild), and compared to healthy children (n = 18). Children with asthma, regardless of the severity of disease, presented similar sensitivity to GCs when compared to healthy children. Patients with mild asthma showed significantly less sensitivity to dexamethasone and children with severe asthma had similar sensitivity to dexamethasone when compared to controls. CONCLUSIONS: In vitro insensitivity to GCs was not demonstrated in children with controlled persistent asthma, even in those with severe disease. Our findings suggest that resistance to GCs in older patients with severe asthma might be an acquired process. However, future longitudinal studies are necessary to confirm this hypothesis.

Interplay between neuroimmunoendocrine systems during post-traumatic stress disorder: a minireview.

Early life stress has been suggested to mediate vulnerability to affective disorders. Traumatic events experienced in childhood such as sexual abuse and/or physical neglect may lead to psychiatric diseases in adult life, including post-traumatic stress disorder (PTSD). Previous studies have focused on adult traumatic events and very little is known regarding the long-term physiological effects of early life stress. Here, we review the complex interplay between most important cognitive, neuroendocrine and immunological changes reported in PTSD, focusing on long-term implications of childhood maltreatment. PTSD has been associated with significant biological changes related to impaired cognitive functions, attenuated hypothalamic-pituitary-adrenal (HPA) axis function (hypocortisolism) and activation of innate immune responses (low-grade inflammation).

Neuroendocrine and immunological correlates of chronic stress in 'strictly healthy' populations.

BACKGROUND: Chronic stress has been associated with detrimental or maladaptive neuroendocrine and immunological changes. OBJECTIVES: We assessed the neuroendocrine and immunological correlates of a realistic chronic stress experienced by strictly healthy caregivers of Alzheimer's disease patients and age-matched controls. METHODS: We screened 330 caregivers and 206 non-caregivers according to the 'strictly healthy' conditions established by the SENIEUR protocol. Forty-one strictly healthy caregivers (60.56 +/- 16.56 years) and 33 non-stressed controls (60.27 +/- 14.11 years) were selected for this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at multiple points by radioimmunoassay. Peripheral T cell proliferation and cellular sensitivity to glucocorticoids (corticosterone and dexamethasone, DEX) were evaluated by colorimetric assays. We also examined the hypothalamic-pituitary-adrenal (HPA) axis response to the administration of a low-dose DEX in vivo. RESULTS: The caregivers were significantly more stressed, anxious and depressed than non-caregivers (all p < 0.0001), in contrast to similar cortisol levels. Caregivers had reduced DHEAS levels (-32%, p < 0.0001), an increased cortisol/DHEAS ratio (39.7%, p < 0.0001) and impaired HPA axis response to DEX intake. Caregivers had a higher T cell proliferation (p < 0.0001) and increased sensitivity to glucocorticoids in vitro (p < 0.01) as compared to non-stressed controls. CONCLUSIONS: Our results suggest that the maintenance of health in chronically stressed populations may be associated with both protective and detrimental neuroendocrine and immunological changes.

The interplay between immunosenescence and age-related diseases.

The aging immune system (immunosenescence) has been implicated with increased morbidity and mortality in the elderly. Of note, T cell aging and low-grade inflammation (inflammaging) are implicated with several age-related conditions. The expansion of late-differentiated T cells (CD28-), regulatory T cells, increased serum levels of autoantibodies, and pro-inflammatory cytokines were implicated with morbidities during aging. Features of accelerated immunosenescence can be identified in adults with chronic inflammatory conditions, such as rheumatoid arthritis, and are predictive of poor clinical outcomes. Therefore, there is an interplay between immunosenescence and age-related diseases. In this review, we discuss how the aging immune system may contribute to the development and clinical course of age-related diseases such as neurodegenerative diseases, rheumatoid arthritis, cancer, cardiovascular, and metabolic diseases.

Increased soluble tumor necrosis factor-alpha receptors in patients with major depressive disorder.

AIM: Several lines of evidence suggest that major depressive disorder is associated with an inflammatory status. Tumor necrosis factor-alpha has been investigated as a potential molecular target in mood disorders. Tumor necrosis factor-alpha exerts its activity through binding to specific cell membrane receptors named as TNFR1 and TNFR2. The aim of the present study was to investigate soluble plasma TNFR1 (sTNFR1) and TNFR2 levels (sTNFR2) in major depressive disorder patients. METHODS: Female outpatients with major depressive disorder (n = 30) were compared with a healthy control group (n = 19). Severity of depressive symptoms was evaluated on Beck Depression Inventory; post-traumatic stress disorder (PTSD) symptoms were evaluated on PTSD Checklist-Civilian Version; and childhood abuse and neglect on the Childhood Trauma Questionnaire. Plasma tumor necrosis factor-alpha and its soluble receptors were measured by ELISA. RESULTS: Patients had no changes in tumor necrosis factor-alpha concentrations but did have increased sTNFR1 (P < 0.001) and sTNFR2 (P < 0.001) levels compared to controls. Plasma level of sTNFR1 was positively predicted by age (B = 0.25, P = 0.05) and PTSD-like symptoms (B = 0.41, P = 0.002) and plasma levels of sTNFR2 by depression severity (B = 0.67, P < 0.001). CONCLUSIONS: Soluble tumor necrosis factor-alpha receptors could be reliable markers of inflammatory activity in major depression.

Inflammation in psychiatric disorders: what comes first?

Neuropsychiatric disorders (i.e., mood disorders and schizophrenia) and inflammation are closely intertwined, and possibly powering each other in a bidirectional loop. Depression facilitates inflammatory reactions and inflammation promotes depression and other neuropsychiatric disorders. Patients with neuropsychiatric disorders exhibit all cardinal features of inflammation, including increased circulating levels of inflammatory inducers, activated sensors, and inflammatory mediators targeting all tissues. Inflammation may contribute to the pathophysiology and clinical progression of these disorders. Of note, proinflammatory cytokines modulate mood behavior and cognition by reducing brain monoamine levels, activating neuroendocrine responses, promoting excitotoxicity (increased glutamate levels), and impairing brain plasticity. What are the sources of this chronic inflammation? Increasing evidence indicates that changes in neuroendocrine regulation, metabolism, diet/microbiota, and negative health behaviors are important triggers of inflammation. Finally, recent data indicate that early-life stress is associated with overt inflammation prior to the development of neuropsychiatric disorders.

Revisiting inflammation in bipolar disorder.

Bipolar disorder (BD) has been associated with immune changes, and yet their underlying mechanisms are still not fully understood. Here, we review the current state of the field, concerning the inflammatory alterations observed in the periphery and in the central nervous system, followed by a discussion of potential underlying mechanisms. We focus mainly on recently proposed mechanisms including the role of the gut-brain axis, the release of damage-associated molecular patterns (DAMPs), and the genetic and epigenetic mechanisms. BD immunology is an evolving field and current studies indicate this disease is more than a brain disorder, and it can be conceptualized as a multi-system condition.

Cocaine Use Disorder Is Associated With Changes in Th1/Th2/Th17 Cytokines and Lymphocytes Subsets.

Background: Cocaine is a psychostimulant drug with high addictive proprieties. Evidence suggests that cocaine use leads to critical changes in the immune system, with significant effects on T, B, and natural killer (NK) cells and influencing peripheral levels of cytokines. The presence of abstinence-related symptoms during detoxification treatment is known to influence the prognosis. Here, our aim was to investigate immune profiles in women with cocaine use disorder (CUD) according to withdrawal symptoms severity. Methods: Blood samples and clinical data were collected at onset of detoxification treatment of 50 women with CUD. The patients were stratified according to Cocaine Selective Severity Assessment (CSSA) scores in low withdrawal (L-W) and high withdrawal (H-W) categories. In addition, we also included a control group with 19 healthy women as reference to immune parameters. Peripheral blood was collected and lymphocyte subsets were phenotyped by multi-color flow cytometry (B cells, CD4+ T, CD8+ T, NK cells, and different stages of T-cell differentiation). PBMCs from patients and healthy controls were stimulated in vitro with phytohemagglutinin (1%) for 72 h to assess the production of Th1/Th2/Th17 cytokines. Results: Following stimulation, lymphocytes from women with CUD produced increased levels of Th1/Th2/Th17 cytokines. However, higher levels of IL-2 and IL-17 were observed only in the L-W group, while higher levels of IL-6 were detected in the H-W group compared to controls. H-W group showed lower percentage of early-differentiated Th cells (CD4+CD27+CD28+), elevated percentage of Th cells (CD3+CD4+), intermediate-differentiated Th cells (CD4+CD27-CD28+), and B cells (CD3-CD19+). Both CUD groups showed decreased percentages of naïve T cells (CD3+CD4+CD45RA+ and CD3+CD8+CD45RA+). Conclusion: Our data demonstrated that CUD can lead to increased production of Th1/Th2/Th17 cytokines and lymphocyte changes.