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Background: The intracellular NOD-like receptor (NLR) family of pathogen recognition receptors (PRRa) is involved in initiating the innate immune response of which NOD1 and NOD2 are the best-characterized members. Aberrant expression of NOD1 and NOD2 has been uncovered in a number of chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis. However, the mechanism underlying NOD1/NOD2 gene expression regulation is still in its infancy. Epigenetic modifications such as DNA methylation and histone acetylation regulate the expression of genes and alterations in their patterns have been linked to many inflammatory diseases. This study investigated whether epigenetic modifying drugs affect the regulation of NOD1/NOD2 activity and expression. DNA methyltransferase inhibitors have recently been used in the treatment of myelodysplastic syndrome and as combination therapy in cancer but the full extent of their effects has not been quantified. Methods: Pharmacological inhibition of epigenetic enzymes in a human monocytic THP-1 cell line was carried out and NOD1/NOD2 expression and pro-inflammatory responses were quantified. Results: Cells primed with a DNA methyltransferase inhibitor (but not a histone deacetylase [HDAC] inhibitor) were found to be consistently more responsive to NOD1/NOD2 stimulation and had increased basal expression. Conclusion: The novel experimentation carried out here suggests for the first time that NOD1/NOD2 receptor activity and expression in monocytes are possibly regulated directly by DNA methylation.

Schizophrenia is a complex psychiatric disorder that includes positive and negative symptoms but also debilitating cognitive deficits. Current pharmacological interventions do not target these deficits. Recent evidence suggests a connection between some inflammatory markers (including C-reactive protein) and cognitive impairment, but did not address other inflammatory markers. In the current study, we try to fill the gap by focusing on the association of Interleukin-6 (IL-6), IL-1β, Tumor Necrosis Factor-α and CRP with cognitive dysfunction.PUBMED and Web of Science databases were searched for all studies published until July 2022. A total of 25 studies were included in an analysis of the association between cognitive performance and variation in IL-6, IL-1β, TNF-α and CRP.A total of 2398 patients were included in this study. Meta-analyses results showed a significant inverse relationship between performance in five cognitive domains (attention-processing speed, executive function, working memory, verbal and visual learning and memory) and systemic IL-6, IL-1β, TNF-α and CRP plasma levels in patients with schizophrenia. The meta-analyses results showed a significant decline in the cognitive performances with the evaluated inflammatory markers with effect sizes ranging from -0.136 to -0.181 for IL-6, -0.188 to -0.38 for TNF-α -0.372 to -0.476 for IL-1β and - 0.168 to -0.311 for CRP.Findings from the current study shows that cognitive deficits are reflective of elevated proinflammatory biomarkers (IL-6, IL-1β, TNF-α and CRP) levels. The results obtained indicate relatedness between inflammation and cognitive decline in patients with schizophrenia. Understanding the underlying pathways between them could have a significant impact on the disease progression and quality of life in schizophrenia patients.

Objective Immune system dysregulation is hypothesised to be central to the aetiopathogenesis of schizophrenia; however, the role of sterile inflammation remains unclear. Damage associated molecular patterns are key initiators of sterile inflammation and are detectable in peripheral blood.Methods A defined systematic search of the Web of Science, PubMed, and Scopus was performed to identify adult case-control studies published between January 1990 and June 2022. Three studies consisting of 242 cases and 83 controls met inclusion for the systematic review and meta-analysis of HMGB1 while twenty-eight studies consisting of 1,544 cases and 1,248 healthy controls were included for S100B.Results A significant standardised mean difference in peripheral S100B and HMGB1 concentrations was detected between cases and controls. S100B subgroup analysis determined the largest significant effect size for unmedicated individuals diagnosed with schizophrenia.Conclusion This study provides evidence that peripheral S100B and HMGB1 concentrations are elevated in individuals diagnosed with schizophrenia when compared with healthy controls. These results should be interpreted with caution as significant heterogeneity was present during meta-analysis of S100B in the entire sample and in sub-group analysis. The persistence of significant heterogeneity throughout subgroup analysis indicates that the current diagnostic groupings may be a barrier to understanding human behaviours and emotions.

Toll-like receptors (TLRs) receptors are responsible for initiation of inflammatory responses by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) or in molecules released following tissue damage in disease states. Expressed in the intestinal epithelium, they initiate an intracellular signalling cascade in response to molecular patterns resulting in the activation of transcription factors and the release of cytokines, chemokines and vasoactive molecules. Intestinal epithelial cells are exposed to microorganisms on a daily basis and form part of the primary defence against pathogens by using TLRs. TLRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. TLRs have more recently been associated with chronic inflammatory diseases as a result of inappropriate regulation, this can be damaging and lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD). Targeting Toll-like receptors offers a potential therapeutic approach for IBD. In this review, the current knowledge on the TLRs is reviewed along with their association with intestinal diseases. Finally, compounds that target TLRs in animal models of IBD, clinic trials and their future merit as targets are discussed.

Animal models of Parkinson’s disease, in which the human α-synuclein transgene is overexpressed in the nigrostriatal pathway using viral vectors, are widely considered to be the most relevant models of the human condition. However, although highly valid, these models have major limitations related to reliability and variability, with many animals exhibiting pronounced α-synuclein expression failing to demonstrate nigrostriatal neurodegeneration or motor dysfunction. Therefore, the aim of this study was to determine if sequential intra-nigral administration of AAV-α-synuclein followed by the small α-synuclein aggregating molecule, FN075, would enhance or precipitate the associated α-synucleinopathy, nigrostriatal pathology and motor dysfunction in subclinical models. Rats were given unilateral intra-nigral injections of AAV-α-synuclein (either wild-type or A53T mutant) followed four weeks later by a unilateral intra-nigral injection of FN075, after which they underwent behavioral testing for lateralized motor functionality until they were sacrificed for immunohistological assessment at 20 weeks after AAV administration. In line with expectations, both of the AAV vectors induced widespread overexpression of human α-synuclein in the substantia nigra and striatum. Sequential administration of FN075 significantly enhanced the α-synuclein pathology with increased density and accumulation of the pathological form of the protein phosphorylated at serine 129 (pS129-α-synuclein). However, despite this enhanced α-synuclein pathology, FN075 did not precipitate nigrostriatal degeneration or motor dysfunction in these subclinical AAV models. In conclusion, FN075 holds significant promise as an approach to enhancing the α-synuclein pathology in viral overexpression models, but further studies are required to determine if alternative administration regimes for this molecule could improve the reliability and variability in these models.

Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson's disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson's disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson's disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p 0.001) and astrocytosis (p 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p 0.05); and precipitated a significant impairment in forelimb kinesis (p 0.01) and sensorimotor integration (p 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson's disease.

During the current coronavirus disease 2019 (COVID-19) pandemic, there has been noticeable increase in the reporting of neurological symptoms in patients. There is still uncertainty around the significance and long-term consequence of these symptoms. There are also many outstanding questions on whether the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) can directly infect the central nervous system (CNS). Given the long association between viral infections with neurodegenerative conditions such as Parkinson’s disease (PD), it seems timely to review this literature again in the context of the COVID-19 pandemic and to glean some useful information from studies on similar viruses. In this commentary, we will consider the current knowledge on viral infections in the brain. In addition, we review the link between viral infection and neurodegeneration in PD, and review the recent literature on SARS infections, the potential link with PD and the potential areas of study in the future.

Toll-like receptors (TLRs) receptors are responsible for initiation of inflammatory responses by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) or in molecules released following tissue damage in disease states. Expressed in the intestinal epithelium, they initiate an intracellular signalling cascade in response to molecular patterns resulting in the activation of transcription factors and the release of cytokines, chemokines and vasoactive molecules. Intestinal epithelial cells are exposed to microorganisms on a daily basis and form part of the primary defence against pathogens by using TLRs. TLRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. TLRs have more recently been associated with chronic inflammatory diseases as a result of inappropriate regulation, this can be damaging and lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD). Targeting Toll-like receptors offers a potential therapeutic approach for IBD. In this review, the current knowledge on the TLRs is reviewed along with their association with intestinal diseases. Finally, compounds that target TLRs in animal models of IBD, clinic trials and their future merit as targets are discussed.

Objective This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults. Methods Using cross-sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults. Results Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition. Conclusion The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long-term effects of childhood adversities.

Background Cognitive difficulties are experienced frequently in schizophrenia (SZ) and are strongly predictive of functional outcome. Although severity of cognitive difficulties has been robustly associated with early life adversity, whether and how they are affected by current stress is unknown. The present study investigated whether acute stress reactivity as measured by heart rate and mood changes predict cognitive performance in patients with schizophrenia and healthy individuals, and whether this is moderated by diagnosis and previous childhood trauma exposure. Methods One hundred and four patients with schizophrenia and 207 healthy participants were administered a battery of tasks assessing cognitive performance after psychosocial stress induction (Trier Social Stress Test; TSST). Mood states (Profile of Mood States; POMS) and heart rate were assessed at baseline, immediately before, and after the TSST. Results Both healthy participants and patients showed increases in POMS Tension and Total Mood Disturbance scores between Time Point 2 (pre-TSST) and Time Point 3 (post-TSST). These changes were not associated with variation in cognition. Although childhood trauma exposure was associated with higher stress reactivity and poorer cognitive function in all participants, childhood trauma did not moderate the association between stress reactivity and cognition. Neither was diagnosis a moderator of this relationship. Discussion These findings suggest that while chronic stress exposure explains significant variation in cognition, acute stress reactivity (measured by changes in Tension and Total Mood Disturbance) did not. In the context of broader developmental processes, we conclude that stressful events that occur earlier in development, and with greater chronicity, are likely to be more strongly associated with cognitive variation than acute transient stressors experienced in adulthood.

The intestinal epithelium consists of a barrier one cell thick found along the length of the gastrointestinal tract composed of many cell subtypes such as absorptive enterocytes and secretory Paneth cells, Goblet cells and enteroendocrine cells. Primarily known as a cell layer used to absorb nutrients from the products of digestion and as a protective barrier from infection, this has changed in recent years with numerous discoveries indicating its importance in priming and tolerising immune cells. Toll-like receptors are a family of pathogen recognition receptors that are widely expressed in human cells including the intestinal epithelium and are known primarily as initiators of inflammatory responses. However, recent evidence suggest that they may have a variety of roles and are involved in cross-talk with a variety of cell types. This review discusses TLR signalling pathways in the context of the intestinal epithelial microenvironment, namely innate and adaptive immune cells as well as microorganisms that resident in the lumen of the gut. TLR signalling is not only involved in defence against such microorganisms but also in communicating with the underlying immune cells. This review describes the many mechanisms by which such communication is executed. It also highlights potential sources of variation in such signalling in the general population in particular the effects of genetic variation, diversity of the microbiota, concomitant disease, diet and age.

Pattern recognition receptors (PRRs) are a key part of the innate immune system, the body's first line of defense against infection and tissue damage. This superfamily of receptors including Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin-like receptors (CLRs) and RIG-like receptors (RLRs) are responsible for initiation of the inflammatory response by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) during infection or in molecules released following tissue damage during acute or chronic disease states (such as sepsis or arthritis). These receptors are widely expressed and located on the cell surface, in intracellular compartments or in the cytoplasm can detect a single or subset of molecules including lipoproteins, carbohydrates or nucleic acids. In response, they initiate an intracellular signaling cascade that culminates in the synthesis and release of cytokines, chemokines and vasoactive molecules. These steps are necessary to maintain tissue homeostasis and remove potentially dangerous pathogens. However, during extreme or acute responses or during chronic disease, this can be damaging and even lead to death. Therefore, it is thought that targeting such receptors may offer a therapeutic approach in chronic inflammatory diseases or in cases of acute infection leading to sepsis. Herein, the current knowledge on the molecular biology of PRRs is reviewed along with their association with inflammatory and infectious diseases. Finally, the testing of therapeutic compounds and their future merit as targets is discussed.

Pattern recognition receptors (PRRs) are a key part of the innate immune system, the body's first line of defense against infection and tissue damage. This superfamily of receptors including Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin-like receptors (CLRs) and RIG-like receptors (RLRs) are responsible for initiation of the inflammatory response by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) during infection or in molecules released following tissue damage during acute or chronic disease states (such as sepsis or arthritis). These receptors are widely expressed and located on the cell surface, in intracellular compartments or in the cytoplasm can detect a single or subset of molecules including lipoproteins, carbohydrates or nucleic acids. In response, they initiate an intracellular signaling cascade that culminates in the synthesis and release of cytokines, chemokines and vasoactive molecules. These steps are necessary to maintain tissue homeostasis and remove potentially dangerous pathogens. However, during extreme or acute responses or during chronic disease, this can be damaging and even lead to death. Therefore, it is thought that targeting such receptors may offer a therapeutic approach in chronic inflammatory diseases or in cases of acute infection leading to sepsis. Herein, the current knowledge on the molecular biology of PRRs is reviewed along with their association with inflammatory and infectious diseases. Finally, the testing of therapeutic compounds and their future merit as targets is discussed.

Nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs) are a family of 23 receptors known as pattern recognition receptors; they are expressed in many cell types and play a key role in the innate immune response. The NLRs are activated by pathogen-associated molecular patterns, which include structurally conserved molecules present on the surfaces of bacteria. The activation of these NLRs by pathogens results in the downstream activation of signalling kinases and transcription factors, culminating in the transcription of genes coding for pro-inflammatory factors. Expression of NLR is altered in many cellular, physiological and disease states. There is a lack of understanding of the mechanisms by which NLR expression is regulated, particularly in chronic inflammatory states. Genetic polymorphisms and protein interactions are included in such mechanisms. This review seeks to examine the current knowledge regarding the regulation of this family of receptors and their signalling pathways as well as how their expression changes in disease states with particular focus on NOD1 and NOD2 in inflammatory bowel diseases among others.

In addition to its role in regulating energy homeostasis, the adipokine, leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder, irritable bowel syndrome (IBS), circulating leptin levels are reported to differ from healthy controls. Additionally, IBS patients display altered cytokine profiles, including elevated circulating levels of the pro-inflammatory cytokine, interleukin (IL)-6, which bears structural homology and similarities in intracellular signalling to leptin. This study aims to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorpto-secretory function were assessed in organ baths and Ussing chambers in Sprague Dawley rat colons. Calcium imaging and immunohistochemical techniques were employed to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6 evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients. This article is protected by copyright. All rights reserved

Highlights • IL-6 has been associated with poorer facial emotion recognition. • fMRI was performed during a faces task and IL-6 measured from blood samples. • IL-6 predicted increased neural response during facial emotion recognition., Background Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. Methods Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. Results Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p

Background While traumatic childhood experiences have been frequently associated with adverse effects on social cognitive abilities, specifically emotion recognition, in individuals with schizophrenia (SZ) and to some degree in healthy adults also (Rokita et al., 2018), the neural mechanisms for this association remain unclear. Therefore, the main aim of this study was to explore the impact of childhood trauma on brain structures that are particularly sensitive to stress and are involved in emotion recognition processes (i.e. amygdala, hippocampus, anterior cingulate cortex (ACC)) (Cancel et al., 2019). We also investigated whether volumetric changes in these brain regions mediate the association between childhood trauma and performance on an emotion recognition task. Methods We investigated 46 patients with SZ (mean age=43.74; SD=10.94; 12 females and 34 males) and 112 healthy adults (mean age=40.13; SD=12.46; 31 females and 81 males). All participants underwent an MRI scan and completed the Childhood Trauma Questionnaire (CTQ) (Bernstein et al., 2003), which assesses the experience of trauma in childhood, including emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. Emotion recognition was measured with the total score on the Emotion Recognition Task (ERT) implemented in the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Robbins et al., 1994). Mediation analyses were conducted to explore the direct and indirect effects of childhood trauma on emotion recognition via volumetric changes in the amygdala, hippocampus and the ACC as mediators. Results We found that patients with SZ had significantly higher scores on physical neglect (PN; p=.018) and cumulative childhood trauma (p=.049) compared to healthy participants. Patients also had significantly smaller hippocampus (p=.001), but not amygdala (p=.453) or ACC (p=.893), and performed worse on the ERT task (p Discussion Our findings provide further evidence for the detrimental impact of childhood trauma, specifically physical neglect, on volumetric changes in the ACC region in both patients with SZ and healthy adults. Moreover, to the best of our knowledge, this is the first study to show that the ACC region may be a potential neural mediator in the association between physical neglect and the ability to recognise emotions. These findings highlight the need to develop early interventions (e.g. parenting programs) in order to minimise the occurrence of childhood adversities, hence preventing from their detrimental effects on brain structure and function in both clinical and non-clinical populations.

Background: Pattern recognition receptors form an essential part of the host defenses against pathogens, in particular in the intestinal epithelium. However, despite their importance relatively little is understood about the regulation of their expression. Increasing evidence suggesting that epigenetic mechanisms such as DNA methylation and histone acetylation have substantial effects on gene expression and regulation. Epigenetic modifying drugs are now used to treat certain cancers but not a lot is known about their effects on the innate immune system. Thus, we set out to examine the role of such drugs in the expression and function of Toll-like receptors. Methods: Using the HCT116 epithelial cell line, we determined the effects of genetic knockout of the DNA methyltransferases enzymes (DNMTs), as well as pharmacological inhibition of the DNMTs and histone deacetylase complexes (HDACs) on TLR responses to their ligands. Results: Our initial results showed that anti-viral responses were affected by changes in the epigenome, with TLR3 responses showing the most dramatic differences. We determined that inhibition of methylation and acetylation inhibited poly I:C induced increases in signaling protein phosphorylation, as well as increases in cytokine mRNA expression and release. We also observed that treatment with epigenetic modifying drugs were leading to large increases in IRF8 expression, a protein that is a known negative regulator of TLR3. When we overexpressed IRF8 in our WT cells we noticed inhibition of poly I:C responses. Conclusion: This research highlighted the potential immunoregulatory role of epigenetic modifying drugs specifically in response to viral stimulation.

Despite over 200 years since its first description by James Parkinson, the cause(s) of most cases of Parkinson’s disease (PD) are yet to be elucidated. The disparity between the current understanding of PD symptomology and pathology has led to numerous symptomatic therapies, but no strategy for prevention or disease cure. An association between certain viral infections and neurodegenerative diseases has been recognized, but largely ignored or dismissed as controversial, for decades. Recent epidemiological studies have renewed scientific interest in investigating microbial interactions with the central nervous system (CNS). This review examines past and current clinical findings and overviews the potential molecular implications of viruses in PD pathology.

Because Toll-like receptors (TLRs) are emerging as potential targets for anti-inflammatory intervention in neurodegenerative diseases, the aim of this study was to characterise the time-course of TLR expression in neurotoxic, environmental and inflammatory Parkinson's disease models. Male Sprague Dawley rats were given intra-striatal injections of 6-hydroxydopamine (10μg), rotenone (1.25μg), LPS (10μg) or Poly I:C (20μg) and were sacrificed on Days 1, 4, 14 and 28 post surgery. Changes in the expression of several inflammatory markers, including TLR3, TLR4 and selected cytokines, were examined using qRT-PCR. We found pronounced changes in the bacterial responsive TLR4 and the viral responsive TLR3 receptors in the inflamed striatum in all models, regardless of whether the challenge was neurotoxic, environmental or inflammatory in nature. However, the magnitude and time-course of changes in expression was different between the different models. This study highlights the pattern of changes in TLR expression in models of Parkinson's disease, and further strengthens the rationale for targeting TLRs for anti-inflammatory intervention in this neurodegenerative disease.

Background Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology; although infection and inflammation have recently been considered as important etiologic agents. A recent meta-analysis showed correlations between cytokine [interleukin-10 (IL-10) and tumor necrosis factor (TNF)] gene polymorphisms and IBS; however, it is still unknown whether patients with IBS have different cytokine profiles compared to healthy population. Methods To determine the relationships between serum/plasma levels or mucosal expression of IL-10/TNF-α and IBS, we conducted a systematic review and meta-analysis based on case–control studies retrieved from PubMed and EMBASE search through August 2013. Standardized mean difference (SMD) was generated by using the inverse variance method. Heterogeneity was assessed based on I2 values. Key Results Serum/plasma levels of TNF-α tended to be higher in IBS vs controls (p = 0.09); this reached significance in IBS subtypes vs controls and in female patients with IBS. However, serum/plasma levels of IL-10 were not significantly different in IBS patients vs controls. Further analysis of serum/plasma IL-10 levels in IBS subtypes did not show any difference; however, analysis based on gender showed a significantly lower serum/plasma IL-10 levels in male patients with IBS vs male controls (p = 0.02). Colonic IL-10 mRNA had a significantly lower expression in IBS vs control (p = 0.001). Conclusions & Inferences There is an imbalance of proinflammatory TNF-α, and anti-inflammatory IL-10, cytokines in IBS. Stratifying IBS patients based on cytokine profile may represent an opportunity for personalized treatment of this condition.

What is the central question of this study? Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons, and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome? What is the main finding and its importance? Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague-Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

BackgroundIncreasing evidence indicates that childhood trauma is a risk factor for schizophrenia and patients with this syndrome have a pro-inflammatory phenotype. We tested the hypothesis that the pro-inflammatory phenotype in schizophrenia is associated with childhood trauma and that patients without a history of such trauma have a similar immune profile to healthy controls.MethodWe recruited 40 schizophrenia patients and 40 controls, all of whom completed the Childhood Trauma Questionnaire (CTQ). Using enzyme-linked immunosorbent assay (ELISA) techniques, we measured peripheral levels of interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor (TNF)-α. These immune parameters were compared in schizophrenia with childhood trauma, schizophrenia without childhood trauma and healthy controls.ResultsPatients with childhood trauma had higher levels of IL-6 and TNF-α than patients without trauma and healthy controls, and TNF-α levels correlated with the extent of the trauma. Patients with no trauma had similar immune profiles to controls.ConclusionsChildhood trauma drives changes, possibly epigenetic, that generate a pro-inflammatory phenotype.

Background: Toll-like receptors (TLRs) are pattern recognition receptors that play an important role as mediators of innate immunity. Human studies have shown changes in endometrial TLR expression during the menstrual cycle and during pregnancy. Our objective was to measure peripheral TLR activity over the course of the menstrual cycle. Methods: We recruited 11 healthy females, and using ELISA we measured sex hormone levels and IL-1β, IL-6, IL-8 and TNF-α following stimulation of whole blood with different TLR agonists during follicular, and early and late luteal phases of the menstrual cycle. Results: During the follicular phase, we observed lower levels of IL-6 and TNF-α following stimulation with the TLR2 agonist HKLM when compared with the early luteal phase; lower levels of IL-1β, IL-6 and TNF-α following stimulation with the TLR4 agonist LPS, and lower levels of IL-1β and TNF-α following stimulation with the TLR5 agonist flagellin. Decreased IL-6 levels in the late compared to the early luteal phase were also observed following stimulation with the TLR5 agonist flagellin. Compared with the follicular phase, the late luteal phase of the cycle resulted in decreased levels of IL-1β and TNF-α following stimulation with the TLR1/TLR2 agonist Pam3CSK and the TLR6/TLR2 agonist FSL1, as well as decreased levels of TNF-α following stimulation with the TLR8 agonist ssRNA40. There were no differences in cytokine release across the menstrual cycle following stimulation with the TLR3 agonist polyriboinosinic polyribocytidylic acid, or the TLR7 agonist Imiquimod. Conclusion: This study is the first to demonstrate that TLR responsivity in peripheral blood fluctuates throughout the menstrual cycle.

Background: This paper seeks to investigate differences between the neonatal and adult retinal ganglion cell populations to apoptotic death stimuli. Design and Samples: In vitro and ex vivo paradigms involving P6 and P60 Sprague–Dawley rat retinal explants and retinal ganglion cells were employed. Methods: Postnatal day 6 (P6) and 60 (P60) Sprague–Dawley retinal ganglion cells and retinal explants were either serum starved or subjected to excitotoxicity using calcium ionophore A23187. Main Outcome Measures: Apoptosis was detected in both models using terminal dUTP nick end labelling. Expression of Apaf-1, active caspases-3 and 9 in P6 and P60 retinas, and in the ganglion cell layer was examined using Western blotting. Results: In both the dissociated retinal ganglion cell and retinal explant models, P60 retinal ganglion cells were significantly less susceptible to excitoxicity and serum starvation than their P6 counterparts. Western blotting indicated that active caspase-3 and Apaf-1 are downregulated in the Sprague–Dawley rat retina at P60 compared with P6 Conclusions: We demonstrate that neonatal Sprague–Dawley retinal ganglion cells are more susceptible to glaucoma-related death stimuli than their adult counterparts in dissociated retinal ganglion cells and axotomized retinal explant models. It is apparent that these different retinal ganglion cell populations are inherently designed to react differently to death stimuli. Thus caution should be exercised when noting the high susceptibility of neonatal retinal ganglion cells to glaucomatous death stimuli.

Aliment Pharmacol Ther 2011; 33: 1045–1052 Summary Background Irritable bowel syndrome (IBS) is a stress-related disorder with disturbed brain-gut communication, gastrointestinal homeostasis and, based on recent evidence, low grade inflammation and an altered microbiota. The immune system is a critical regulator of the brain-gut axis. Toll-like receptors (TLRs) are pattern recognition molecules regulating innate immunity. Aim To characterise toll-like receptor activity in IBS. Methods Thirty IBS patients and 30 healthy controls (HC) were recruited. Venous blood was collected, and cultured with a panel of toll-like receptor agonists for 24 h. Cell supernatants were analysed using a multiplex ELISA approach to measure IL1β, IL6, IL8 and TNFα. Plasma was analysed for levels of inflammatory cytokines and cortisol. Results Toll-like receptor agonist-induced cytokine (IL1β, IL6, IL8 and TNFα) release was markedly enhanced in stimulated whole blood from IBS (n = 30) patients compared with healthy controls (n = 30). An exaggerated response to the TLR8 agonist for all cytokines investigated was seen in IBS patients. In addition, enhanced TLR2-induced TNFα release, TLR3-induced IL-8 release, TLR4-induced IL1β and TNFα release, TLR5-induced IL1β and TNFα release and TLR7-induced IL-8 release were also observed in IBS patients. No differences in TLR1, TLR6 or TLR9 activity were detected. In addition, plasma levels of cortisol, IL-6 and IL-8 were significantly increased in IBS patients. Conclusion Taken together, these data demonstrate elevated cytokine levels and toll-like receptor activity in the periphery of patients with the irritable bowel syndrome, indicating some immune dysregulation in these patients.

Irritable bowel syndrome (IBS) is a functional disorder that is associated with a number of extra-intestinal co-morbidities and a pro-inflammatory profile. This study was designed to examine the cytokine profile among a group of IBS patients with the extra-intestinal co-morbidities fibromyalgia, premenstrual dysmorphic disorder, and chronic fatigue syndrome.In all, 100 female IBS patients with these co-morbidities, 21 IBS subjects without co-morbidity ("pure" IBS; Rome II), and 54 age-matched female controls took part in the study. Blood was drawn for measurement of the plasma cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)α, and interferon γ. The presence of the selected extra-intestinal manifestations was assessed using standard international criteria.Patients with IBS have increased plasma levels of IL-6 and IL-8; those with these extra-intestinal co-morbidities were found to have, in addition, increased levels of IL-1β and TNFα. No associations were evident between cytokine profiles and the nature of the co-morbidity or number of extra-intestinal co-morbidities present.Although IBS is characterized by a pro-inflammatory profile featuring the pro-inflammatory cytokines IL-6 and IL-8, IBS patients with certain extra-intestinal co-morbid conditions are distinguished by additional elevations in IL-1β and TNFα.

Apoptosis or programmed cell death is a critical regulator of tissue homeostasis and emerging evidence is focused on the role of apoptosis mechanisms in the central nervous system. Generally, apoptosis is necessary to prevent cancerous growths. However, excessive apoptosis in post-mitotic cells such as neurons leads to neurodegeneration. Chronic stress, which can precipitate depression, has been shown to increase the susceptibility of certain populations of neurons to cell death while antidepressant treatment, in general, shows the ability to oppose these effects and promote neuroprotection. Here, we discuss the major players in cell death pathways, the physiological implications of chronic stress and depression, chronic stress models in animals which result in cell death and the different classes of antidepressants and mood stabilizers that have been shown to prevent cell death. We discuss the cellular effects of antidepressants and possible modes of action in preventing apoptosis. Investigations on the role of apoptosis in mediating the molecular, physiological and behavioural effects of antidepressants may help gain a better mechanistic insight into drug action and allow refinement of current therapeutics in order to target these pathways in a specific manner.

Optic nerve transection results in the death of retinal ganglion cells (RGCs) by apoptosis. Apoptosis is regulated by the Bcl-2 family of proteins, of which the Bcl-2 homology (BH3) -only proteins forms a subset. As BH3-only proteins have been shown to play a significant role in regulating cell death in the central nervous system, we wished to investigate the role of Bcl-2 interacting mediator of cell death (Bim), a prominent member of this protein family in the regulation of cell death in the RGC layer using in vitro retinal explants. In this study, we use an innovative retinal shaving procedure to isolate the cells of the ganglion cell layer to use for western blotting. Members of the BH3-only protein family are down-regulated during retinal development and are not normally expressed in the adult retina. Using this procedure, we demonstrate that Bim is re-expressed and its expression is increased over time following axotomy. Expression of Bad and Bik decreases over the same time course, whereas there is no indication that Bid and Puma are re-expressed. We show that explants from Bim knockout mice are resistant to axotomy-induced death when compared with their wild-type counterparts. Genetic deletion of Bim also prevents caspase 3 cleavage. The activity of Bim can be negatively regulated by phosphorylation. We show that the decrease of Bim phosphorylation correlates with a decrease in expression of survival kinases such as pAkt and pERK over the same time course. These results implicate Bim re-expression as being essential for axotomy-induced death of RGCs and that phosphorylation of Bim negatively regulates its activity in RGCs.

Toll-like receptors (TLRs) are a family of 13 receptors known as pattern-recognition receptors (PRRs) and have a key role in the innate immune response. The TLRs are activated by pathogen-associated molecular patterns (PAMPs) that are structurally conserved molecules present on the surfaces of bacteria and viruses. The activation of these TLRs by pathogens results in the downstream activation of genes involved in the production of proinflammatory factors. There is a lack of understanding on the mechanisms by which TLR gene expression is regulated. Epigenetics could be one such mechanism, which is concerned with changes in gene expression/products that arise without a change in the nucleotide sequence. These changes are brought about by two main mechanisms, DNA methylation and histone modifications. This review seeks to examine the current knowledge regarding the epigenetic regulation of this family of receptors and their signalling pathways.

To discuss the recent landmark findings that have increased our understanding not only of the role of the epithelial cell cycle in the homeostasis of the small intestine, but also its relevance to inflammation and cancer.Recent data have unveiled novel information on protein interactions directly involved in the cell cycle as well as in the pathways that transduce external environmental signals to the cell cycle. A growing body of the recent evidence confirms the importance of food as well as hormonal regulation in the gut on cell cycle. Information on the contribution of the epithelial microenvironment, including the microbiota, has grown substantially in the recent years as well as on the gene-environment interactions and the multiple epigenetic mechanisms involved in regulating cell-cycle proteins and signalling. Finally, further studies investigating the dysregulation of the cell cycle during inflammation and proliferation have increased our understanding of the pathophysiology of chronic inflammatory diseases and cancer.This review highlights some of the most recent advances that further emphasize the importance of the cell cycle in the small intestine during homeostasis as well as in inflammation and cancer.

Episodic bouts of abdominal pain and altered bowel habit are characteristic of irritable bowel syndrome (IBS). Although a comprehensive understanding of IBS pathophysiology remains elusive, support is growing for a primary role for immune activation in disease severity as evidenced by altered cytokine profiles in IBS plasma. Additionally, aberrant stimulation of the stress axis is likely to result in altered plasma constituents.Whole-mount preparations of submucosal plexus from adult male Sprague Dawley rats were exposed to plasma from IBS patients and healthy controls. Ratiometric calcium imaging recordings were used to measure changes in intracellular calcium ([Ca(2+)]i) as a marker of neuronal excitability.IBS plasma stimulated a robust increase in [Ca(2+)]i (0.09 ± 0.02) whereas plasma from healthy volunteers had little effect (-0.02 ± 0.02, n=24, p0.001). The neuromodulatory actions of IBS plasma were reduced by pre-neutralisation with anti-interleukin (IL)-6 (p0.01) but not IL-8, immunoglobulin G or C-reactive protein. Moreover, IBS plasma-evoked responses (0.22 ± 0.06) were inhibited by the corticotrophin releasing factor receptor (CRFR) 1 antagonist, antalarmin (1μM, 0.015 ± 0.02, n=14, p0.05), but not the CRFR2 antagonist, astressin 2B. Neuronal activation was mediated by ERK/MAPK signalling.These data provide evidence that factors present in IBS plasma modulate neuronal activity in the submucosal plexus and that this is likely to involve CRFR1 activation and IL-6 signalling. These neuromodulatory actions of stress and immune factors indicate a potential mechanism by which immune activation during periods of stress may lead to symptom flares in IBS.

IBD includes Crohn's Disease and ulcerative colitis (UC), which are multifaceted chronic inflammatory conditions. Their aetiology is thought to involve the interaction of genetic, immunological and environmental factors. Current therapeutics have not succeeded in eliminating the burden of these diseases. Some are associated with side effects, which themselves can cause discomfort for the patient, leading to a decrease in compliance and a return to the status quo prior to medication. In addition, the cost of current therapeutics is very high.1 All of these considerations require the development of less toxic, better tolerated, more efficacious and cheaper drugs. Enteric glial cells (EGCs) are major constituents of the enteric nervous system, outnumbering neurones by 4–1.2 They are thought to help control motility, secretion, nutrient uptake and blood flow via their interactions with enteric nerves. Evidence of their importance in the transduction of inflammatory signals is now emerging. They are capable of producing many inflammatory cytokines as well as neurokinin A and substance P, which can act on immune cells in their vicinity.2 Glial proliferation is seen in animal models of inflammation, as well as …