Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression.

BACKGROUND: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.

Alterations in B cell subsets correlate with body composition parameters in female adolescents with anorexia nervosa.

Anorexia nervosa (AN) is a severe eating disorder and often associated with altered humoral immune responses. However, distinct B cell maturation stages in peripheral blood in adolescents with AN have not been characterized. Treatment effects and the relationship between clinical and B cell parameters are also not fully understood. Here we investigated the phenotype of circulating B cell subsets and the relationship with body composition in adolescents with AN before (T0, n = 24) and after 6 weeks (T1, n = 20) of treatment. Using multi-parameter flow cytometry, we found increased percentages of antigen-experienced B cells and plasmablasts in patients with AN compared to healthy controls (n = 20). In contrast, percentages of CD1d+CD5+ B cells and transitional B cells with immunoregulatory roles were reduced at T0 and T1. These B cell frequencies correlated positively with fat mass, fat mass index (FMI), free fat mass index, and body mass index standard deviation score. In addition, scavenger-like receptor CD5 expression levels were downregulated on transitional B cells and correlated with fat mass and FMI in AN. Our findings that regulatory B cell subgroups were reduced in AN and their strong relationship with body composition parameters point toward an impact of immunoregulatory B cells in the pathogenesis of AN.

Brain-derived neurotrophic factor, depressive symptoms and somatic comorbidity in patients with coronary heart disease.

OBJECTIVE: Depression and coronary heart disease (CHD) are highly comorbid conditions. Brain-derived neurotrophic factor (BDNF) plays an important role in cardiovascular processes. Depressed patients typically show decreased BDNF concentrations. We analysed the relationship between BDNF and depression in a sample of patients with CHD and additionally distinguished between cognitive-affective and somatic depression symptoms. We also investigated whether BDNF was associated with somatic comorbidity burden, acute coronary syndrome (ACS) or congestive heart failure (CHF). METHODS: The following variables were assessed for 225 hospitalised patients with CHD: BDNF concentrations, depression [Patient Health Questionnaire-9 (PHQ-9)], somatic comorbidity (Charlson Comorbidity Index), CHF, ACS, platelet count, smoking status and antidepressant treatment. RESULTS: Regression models revealed that BDNF was not associated with severity of depression. Although depressed patients (PHQ-9 score >7) had significantly lower BDNF concentrations compared to non-depressed patients (p = 0.04), this was not statistically significant after controlling for confounders (p = 0.15). Cognitive-affective symptoms and somatic comorbidity burden each closely missed a statistically significant association with BDNF concentrations (p = 0.08, p = 0.06, respectively). BDNF was reduced in patients with CHF (p = 0.02). There was no covariate-adjusted, significant association between BDNF and ACS. CONCLUSION: Serum BDNF concentrations are associated with cardiovascular dysfunction. Somatic comorbidities should be considered when investigating the relationship between depression and BDNF.

The modulating impact of cigarette smoking on brain structure in panic disorder: a voxel-based morphometry study.

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD patients (71 smokers) and 178 healthy controls (62 smokers) participated in a multicenter magnetic resonance imaging (MRI) study. T1-weighted images were used to examine brain structural alterations using voxel-based morphometry in a priori defined regions of the defensive system network. PD was associated with gray matter volume reductions in the amygdala and hippocampus. This difference was driven by non-smokers and absent in smoking subjects. Bilateral amygdala volumes were reduced with increasing health burden (neither PD nor smoking > either PD or smoking > both PD and smoking). As smoking can narrow or diminish commonly observed structural abnormalities in PD, the effect of smoking should be considered in MRI studies focusing on patients with pathological forms of fear and anxiety. Future studies are needed to determine if smoking may increase the risk for subsequent psychopathology via brain functional or structural alterations.

Association between heart-focused anxiety, depressive symptoms, health behaviors and healthcare utilization in patients with coronary heart disease.

OBJECTIVE: To analyze the association between heart-focused anxiety, depressive symptoms, health behaviors and healthcare utilization in patients with coronary heart disease (CHD). METHODS: N = 1007 patients with CHD were recruited in hospital and followed for one year in a two-site cohort study. Heart focused anxiety (Cardiac Anxiety Questionnaire [CAQ] with the three subscales fear, attention, and avoidance), depressive symptoms (depression module from the Patient Health Questionnaire [PHQ-9]), health behaviors and healthcare utilization (smoking status, alcohol consumption, physical activity, outpatient physician/psychotherapist visits) were assessed six months after the initial hospitalization. Multiple regression models were used for statistical analysis. RESULTS: About one third of the sample exhibited clinically significant CAQ scores. Higher CAQ-avoidance scores were associated with current smoking (OR = 1.62; 95%CI: 1.33-1.98), reduced alcohol intake (OR = 0.83; 95%CI: 0.71-0.98), non-participation in a coronary exercise group (OR = 1.76; 95%CI: 1.42-2.17), less regular physical activity (OR = 2.69; 95%CI: 2.32-3.12), and more frequent contact to general practitioners (GPs; b = 0.07, SE: 0.03). CAQ-attention was associated with non-smoking (OR = 0.51; 95%CI: 0.37-0.70), exercise group participation (OR = 0.69; 95%CI: 0.51-0.94), more frequent regular physical activity (OR = 0.55; 95%CI: 0.44-0.68), and more frequent contact to specialists for internal medicine (b = 0.09, SE: 0.04). CAQ-fear was not associated with any of the health behavior or healthcare use measures. Depressive symptoms were associated with reduced regular physical activity (OR = 1.05; 95%CI: 1.02-1.08) and increased contact to mental care specialists (b = 0.03, SE: 0.01) and GPs (b = 0.02, SE: 0.01). CONCLUSIONS: Heart-focused anxiety and depressive symptoms may impede secondary prevention in patients with CHD and increase outpatient healthcare utilization.

[Diagnostic Accuracy of German Depression Screenings in Patients with Coronary Heart Disease]. / Erkennungsgüte dreier deutschsprachiger Screeninginstrumente für Depression bei hospitalisierten Patienten mit koronarer Herzerkrankung.

OBJECTIVE: To compare the diagnostic accuracy of German depression screening instruments in patients with coronary heart disease (CHD). METHODS: 1019 CHD patients completed the Patient Health Questionnaire (PHQ-9 and PHQ-2) and the Hospital Anxiety and Depression Scale (HADS-D). The Composite International Diagnostic Interview served as reference standard for "any depressive disorder" and "major depression". RESULTS: The accuracy of the PHQ-9 and the HADS-D was comparable according to the area under the curve, and both were superior to the PHQ-2. The optimal cut-off according to the Youden index (maximum sum of sensitivity and specificity) was 7 for both instruments. At this optimal cut-off, the PHQ-9 had a higher sensitivity compared to the HADS-D, but a lower specificity (below 68). Results remained similar when patients who reported that they currently underwent treatment for depression were excluded. CONCLUSION: The PHQ-9 and the HADS-D have comparable overall diagnostic accuracy in CHD patients. In line with previous screening studies with CHD patients, the optimal cut-offs were below the cut-offs that are recommended in the literature.

Alterations of the Innate Immune System in Susceptibility and Resilience After Social Defeat Stress.

Dysregulation of innate immune responses has frequently been reported in stress-associated psychiatric disorders such as major depression. In mice, enhanced circulating cytokine levels as well as altered innate immune cell numbers have been found after stress exposure. In addition, stress-induced recruitment of peripheral monocytes to the brain has been shown to promote anxiety-like behavior. However, it is yet unclear whether specific differences in the innate immune system are associated with stress susceptibility or resilience in mice. Utilizing chronic social defeat, a model of depression and stress vulnerability, we characterized peripheral and brain-invading myeloid cells in stress-susceptible and resilient animals. In all defeated animals, we found reduced percentages of CD11c+ dendritic cells (DCs) by flow cytometry in the spleen when compared to non-defeated controls. Exclusively in susceptible mice conventional DCs of the spleen showed up-regulated expression of MHC class II and co-stimulatory CD80 molecules pointing toward an enhanced maturation phenotype of these cells. Susceptible, but not resilient animals further exhibited an increase in inflammatory Ly6Chi monocytes and higher numbers of spleen-derived CD11b+ cells that produced the proinflammatory cytokine tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. Increased percentages of peripheral CD45hi CD11b+ cells immigrated into the brain of defeated mice, regardless of resilience or susceptibility. However, cellular infiltrates in the brain of susceptible mice contained higher percentages of CC chemokine receptor 2 (CCR2+) Ly6Chi monocytes representing an inflammatory phenotype. Thus, we defined specific stress-related immune signatures involving conventional DCs and inflammatory Ly6Chi monocytes in susceptible and resilient mice. Together, our findings suggest an impact of the innate immune system in vulnerability to stress-related disorders such as major depression.

Altered B Cell Homeostasis in Patients with Major Depressive Disorder and Normalization of CD5 Surface Expression on Regulatory B Cells in Treatment Responders.

Pro-inflammatory activity and cell-mediated immune responses have been widely observed in patients with major depressive disorder (MDD). Besides their well-known function as antibody-producers, B cells play a key role in inflammatory responses by secreting pro- and anti-inflammatory factors. However, homeostasis of specific B cell subsets has not been comprehensively investigated in MDD. In this study, we characterized circulating B cells of distinct developmental steps including transitional, naïve-mature, antigen-experienced switched, and non-switched memory cells, plasmablasts and regulatory B cells by multi-parameter flow cytometry. In a 6-weeks follow-up, circulating B cells were monitored in a small group of therapy responders and non-responders. Frequencies of naïve lgD+CD27- B cells, but not lgD+CD27+ memory B cells, were reduced in severely depressed patients as compared to healthy donors (HD) or mildly to moderately depressed patients. Specifically, B cells with immune-regulatory capacities such as CD1d+CD5+ B cells and CD24+CD38hi transitional B cells were reduced in MDD. Also Bm1-Bm5 classification in MDD revealed reduced Bm2' cells comprising germinal center founder cells as well as transitional B cells. We further found that reduced CD5 surface expression on transitional B cells was associated with severe depression and normalized exclusively in clinical responders. This study demonstrates a compromised peripheral B cell compartment in MDD with a reduction in B cells exhibiting a regulatory phenotype. Recovery of CD5 surface expression on transitional B cells in clinical response, a molecule involved in activation and down-regulation of B cell responses, further points towards a B cell-dependent process in the pathogenesis of MDD.

Mitochondria, Microglia, and the Immune System-How Are They Linked in Affective Disorders?

Major depressive disorder (MDD) is a severe mood disorder and frequently associated with alterations of the immune system characterized by enhanced levels of circulating pro-inflammatory cytokines and microglia activation in the brain. Increasing evidence suggests that dysfunction of mitochondria may play a key role in the pathogenesis of MDD. Mitochondria are regulators of numerous cellular functions including energy metabolism, maintenance of redox and calcium homeostasis, and cell death and therefore modulate many facets of the innate immune response. In depression-like behavior of rodents, mitochondrial perturbation and release of mitochondrial components have been shown to boost cytokine production and neuroinflammation. On the other hand, pro-inflammatory cytokines may influence mitochondrial functions such as oxidative phosphorylation, production of adenosine triphosphate, and reactive oxygen species, thereby aggravating inflammation. There is strong interest in a better understanding of immunometabolic pathways in MDD that may serve as diagnostic markers and therapeutic targets. Here, we review the interaction between mitochondrial metabolism and innate immunity in the pathophysiology of MDD. We specifically focus on immunometabolic processes that govern microglial and peripheral myeloid cell functions, both cellular components involved in neuroinflammation in depression-like behavior. We finally discuss microglial polarization and associated metabolic states in depression-associated behavior and in MDD.

Serum brain-derived neurotrophic factor and stability of depressive symptoms in coronary heart disease patients: A prospective study.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) supports neurogenesis, angiogenesis, and promotes the survival of various cell types in the brain and the coronary system. Moreover, BDNF is associated with both coronary heart disease (CHD) and depression. The current study aims to investigate whether serum BDNF levels are associated with the course of depressive symptoms in CHD patients. METHODS: At baseline, N=225 CHD patients were enrolled while hospitalized. Of these, N=190 (84%) could be followed up 6 months later. Depressive symptoms were assessed both at baseline and at the 6-months follow-up using the Patient Health Questionnaire (PHQ-9). Serum BDNF concentrations were measured using fluorometric Enzyme-linked immunosorbent assays (ELISA). RESULTS: Logistic regression models showed that lower BDNF levels were associated with persistent depressive symptoms, even after adjustment for age, sex, smoking and potential medical confounders. The incidence of depressive symptoms was not related to lower BDNF levels. However, somatic comorbidity (as measured by the Charlson Comorbidity Index) was significantly associated with the incidence of depressive symptoms. CONCLUSIONS: Our findings suggest a role of BDNF in the link between CHD and depressive symptoms. Particularly, low serum BDNF levels could be considered as a valuable biomarker for the persistence of depressive symptoms among depressed CHD patients.

Impact of major depressive disorder, distinct subtypes, and symptom severity on lifestyle in the BiDirect Study.

The aim of this study was to examine associations of major depressive disorder (MDD), its distinct subtypes, and symptom severity with the individual lifestyle factors smoking, diet quality, physical activity, and body mass index as well as with a combined lifestyle index measuring the co-occurrence of these lifestyle factors. A sample of 823 patients with MDD and 597 non-depressed controls was examined. The psychiatric assessment was based on a clinical interview including the Mini International Neuropsychiatric Interview and the Hamilton Depression Rating Scale. Each lifestyle factor was scored as either healthy or unhealthy, and the number of unhealthy lifestyle factors was added up in a combined lifestyle index. Cross-sectional analyses were performed using alternating logistic regression and ordinal logistic regression, adjusted for socio-demographic characteristics. After adjustment, MDD was significantly associated with smoking, low physical activity, and overweight. Likewise, MDD was significantly related to the overall lifestyle index. When stratifying for subtypes, all subtypes showed higher odds for an overall unhealthier lifestyle than controls, but the associations with the individual lifestyle factors were partly different. Symptom severity was associated with the lifestyle index in a dose-response manner. In conclusion, patients with MDD represent an important target group for lifestyle interventions.

Cytokine levels in major depression are related to childhood trauma but not to recent stressors.

BACKGROUND: Major depressive disorder (MDD) is a stress-related psychiatric disorder. A subgroup of MDD patients is characterized by increased inflammatory activation. We aimed to investigate whether increased inflammation particularly occurs in MDD patients with a history of stressful early or later life experiences. METHODS: Serum levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in N=214 MDD patients and N=180 healthy controls (HC). Childhood trauma (Childhood Trauma Questionnaire - CTQ), adverse life events of the past 12 months (List of Threatening Experiences Questionnaire - LTE-Q), and perceived stress in the past month (Perceived Stress Scale - PSS) were analyzed with regard to cytokine levels. RESULTS: Pro-inflammatory cytokine levels were not related to global scores of adverse events or perceived stress covering different time points ranging from childhood to the past month. However, in the subgroup of traumatized MDD patients, higher severity of childhood sexual abuse was associated with higher levels of both IL-6 and TNF-α in a linear fashion. CONCLUSIONS: Our data suggest a linear relationship between childhood sexual abuse and increased pro-inflammatory cytokine levels in MDD patients, while more recent stressful life events were not related to these inflammatory markers.

Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice.

Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/-)) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior.

Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder?

Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders.

Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder.

BACKGROUND: Bipolar Disorder (BD) is associated with elevated biomarkers of cell-mediated immune activation and inflammation and with signs of widespread disruption of white matter (WM) integrity in adult life. Consistent findings in animal models link WM damage in inflammatory diseases of the brain and serum levels of cytokines. METHODS: With an exploratory approach, we tested the effects of 22 serum analytes, including pro- and anti-inflammatory cytokines and neurotrophic/hematopoietic factors, on DTI measures of WM microstructure in a sample of 31 patients with a major depressive episode in course of BD. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA). RESULTS: The inflammation-related cytokines TNF-α, IL-8, IFN-γ and IL-10, and the growth factors IGFBP2 and PDGF-BB, shared the same significant associations with lower FA, and higher MD and RD, in large overlapping networks of WM fibers mostly located in the anterior part of the brain and including corpus callosum, cingulum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, uncinate, forceps, corona radiata, thalamic radiation, internal capsule. CONCLUSIONS: Higher RD is thought to signify increased space between fibers, suggesting demyelination or dysmyelination. The pattern of higher RD and MD with lower FA suggests that inflammation-related cytokine and growth factor levels inversely associate with integrity of myelin sheaths. The activated inflammatory response system might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.

Molecular serum signature of treatment resistant depression.

RATIONALE: A substantial number of patients suffering from major depressive disorder (MDD) do not respond to multiple trials of anti-depressants, develop a chronic course of disease and become treatment resistant. Most of the studies investigating molecular changes in treatment-resistant depression (TRD) have only examined a limited number of molecules and genes. Consequently, biomarkers associated with TRD are still lacking. OBJECTIVES: This study aimed to use recently advanced high-throughput proteomic platforms to identify peripheral biomarkers of TRD defined by two staging models, the Thase and Rush staging model (TRM) and the Maudsley Staging Model (MSM). METHODS: Serum collected from an inpatient cohort of 65 individuals suffering from MDD was analysed using two different mass spectrometric-based platforms, label-free liquid chromatography mass spectrometry (LC-MS(E)) and selective reaction monitoring (SRM), as well as a multiplex bead based assay. RESULTS: In the LC-MS(E) analysis, proteins involved in the acute phase response and complement activation and coagulation were significantly different between the staging groups in both models. In the multiplex bead-based assay analysis TNF-α levels (log(odds) = -4.95, p = 0.045) were significantly different in the TRM comparison. Using SRM, significant changes of three apolipoproteins A-I (ß = 0.029, p = 0.035), M (ß = -0.017, p = 0.009) and F (ß = -0.031, p = 0.024) were associated with the TRM but not the MSM. CONCLUSION: Overall, our findings suggest that proteins, which are involved in immune and complement activation, may represent potential biomarkers that could be used by clinicians to identify high-risk patients. Nevertheless, given that the molecular changes between the staging groups were subtle, the results need to be interpreted cautiously.

Stem Cell Factor (SCF) is a putative biomarker of antidepressant response.

Growth factors involved in neurogenesis and neuroplasticity could play a role in biological processes that drive depression recovery. Combined total sleep deprivation and morning light therapy (TSD + LT) can acutely reverse depressive symptoms, thus allowing to investigate the neurobiological correlates of antidepressant response. We tested if changes on plasma levels of Brain Derived Neurotrophic Factor (BDNF), S100 calcium binding protein B (S100-B), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Vascular Endothelial Growth Factor (VEGF) are associated with response to TSD + LT in 26 inpatients affected by a major depressive episode in the course of bipolar disorder. Regional grey matter (GM) volumes were assessed at baseline, and BOLD fMRI neural responses to a moral valence decision task were recorded before and after treatment. 61.5 % of patients responded to treatment. SCF plasma levels increased significantly more in responders, and correlated with GM volumes in frontal and parietal cortical areas. The pattern of change of SCF also associated with both GM volumes and changes of BOLD fMRI neural responses in the anterior cingulate and medial prefrontal cortex. SCF is both a hematopoietic growth factor and a neurotrophic factor, involved in neuron-neuron and neuron-(micro) glia interactions, fostering neuronal growth and an anti-inflammatory milieu. We correlated SCF levels with antidepressant response and with functional and structural MRI measures in cortical areas that are involved in the cognitive generation and control of affect. SCF may be a candidate growth factor that contributes to neurotrophic and immune effects that are involved in the process of remission/recovery from depression.

The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts.

AIMS: Acute rejection of cardiac allografts is a major risk factor limiting survival of heart transplant recipients. Rejection is triggered by dendritic cell (DC) mediated activation of host T cells, amongst others CD4(+) T helper (TH)1- and TH17 cells. The cannabinoid receptor 2 (CB2) is an important modulator of cellular immune responses. However, its role in cardiac allograft rejection has not been studied so far. MAIN METHODS: Here, we examined the effect of CB2 on cytokine release by mature DCs and its impact on CD4(+) T cell differentiation by utilizing in vitro generated bone marrow-derived DCs (BM-DCs) and CD4(+) T cells from CB2 knockout (Cnr2(-/-)) mice. We further assessed the functional role of CB2 in acute allograft rejection using Cnr2(-/-) mice in a fully major histocompatibility complex-mismatched mouse cardiac transplantation model. KEY FINDINGS: Cardiac allograft rejection was accelerated in Cnr2(-/-) mice compared to wild type recipients. In vitro stimulation of BM-DCs showed enhanced secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF) and the immunomodulatory cytokine TGF-ß. Furthermore, secretion of the TH1/TH17 promoting cytokines IL-12 and IL-23 was increased in Cnr2(-/-) BM-DCs. In addition, Cnr2(-/-) CD4(+) T cells showed an enhanced capacity to differentiate into interferon (IFN)-γ- or IL-17-producing effector cells. SIGNIFICANCE: These results demonstrate that CB2 modulates in vitro cytokine responses via DCs and directly via its influence on TH1/TH17 differentiation. These findings and the fact that allograft rejection is enhanced in Cnr2(-/-) mice suggest that CB2 may be a promising therapeutic target in organ transplantation.

Association of adenosine receptor gene polymorphisms and in vivo adenosine A1 receptor binding in the human brain.

Adenosine A1 receptors (A1ARs) and the interacting adenosine A2A receptors are implicated in neurological and psychiatric disorders. Variants within the corresponding genes ADORA1 and ADORA2A were shown associated with pathophysiologic alterations, particularly increased anxiety. It is unknown so far, if these variants might modulate the A1AR distribution and availability in different brain regions. In this pilot study, the influence of ADORA1 and ADORA2A variants on in vivo A1AR binding was assessed with the A1AR-selective positron emission tomography (PET) radioligand [(18)F]CPFPX in brains of healthy humans. Twenty-eight normal control subjects underwent PET procedures to calculate the binding potential BPND of [(18)F]CPFPX in cerebral regions and to assess ADORA1 and ADORA2A single nucleotide polymorphism (SNP) effects on regional BPND data. Our results revealed SNPs of both genes associated with [(18)F]CPFPX binding to the A1AR. The strongest effects that withstood even Bonferroni correction of multiple SNP testing were found in non-smoking subjects (N=22) for ADORA2A SNPs rs2236624 and rs5751876 (corr. Pall<0.05). SNP alleles previously identified at risk for increased anxiety like the rs5751876 T-allele corresponded to consistently higher A1AR availability in all brain regions. Our data indicate for the first time that variation of A1AR availability was associated with ADORA SNPs. The finding of increased A1AR availability in regions of the fear network, particularly in ADORA2A risk allele carriers, strongly warrants evaluation and replication in further studies including individuals with increased anxiety.

Gender-specific association of variants in the AKR1C1 gene with dimensional anxiety in patients with panic disorder: additional evidence for the importance of neurosteroids in anxiety?

BACKGROUND: Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes. However, little is known about the contribution of genetic variants in genes relevant for the neurosteroidogenesis to anxiety disorders. METHODS: We performed an association analysis of single nucleotide polymorphisms (SNPs) in five genes related to the neurosteroidal pathway with emphasis on progesterone and allopregnanolone biosynthesis (steroid-5-alpha-reductase 1A (SRD5A1), aldo-keto reductase family 1 C1-C3 (AKR1C1-AKR1C3) and translocator protein 18 kDA (TSPO) with panic disorder (PD) and dimensional anxiety in two German PD samples (cases N = 522, controls N = 1,115). RESULTS: Case-control analysis for PD and SNPs in the five selected genes was negative in the combined sample. However, we detected a significant association of anticipatory anxiety with two intronic SNPs (rs3930965, rs41314625) located in the gene AKR1C1 surviving correction for multiple testing in PD patients. Stratification analysis for gender revealed a female-specific effect of the associations of both SNPs. CONCLUSIONS: These results suggest a modulatory effect of AKR1C1 activity on anxiety levels, most likely through changes in progesterone and allopregnanolone levels within and outside the brain. In summary, this is the first evidence for the gender-specific implication of the AKR1C1 gene in the expression of anticipatory anxiety in PD. Further analyses to unravel the functional role of the SNPs detected here and replication analyses are needed to validate our results.