Schizophrenia patients with a history of childhood trauma have a pro-inflammatory phenotype

Background. Increasing 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. Method. We 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)-1b, IL-6, IL-8 and tumour necrosis factor (TNF)-a. These immune parameters were compared in schizophrenia with childhood trauma, schizophrenia without childhood trauma and healthy controls. Results. Patients with childhood trauma had higher levels of IL-6 and TNF-a than patients without trauma and healthy controls, and TNF-a levels correlated with the extent of the trauma. Patients with no trauma had similar immune profiles to controls. Conclusions. Childhood trauma drives changes, possibly epigenetic, that generate a pro-inflammatory phenotype

Toll-Like Receptor mRNA Expression Is Selectively Increased in the Colonic Mucosa of Two Animal Models Relevant to Irritable Bowel Syndrome

Background: Irritable bowel syndrome (IBS) is largely viewed as a stress-related disorder caused by aberrant brain-gut– immune communication and altered gastrointestinal (GI) homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs) are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stressinduced IBS-like symptoms. Methodology/Principal Findings: In this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensivity; the stress-sensitive Wistar-Kyoto (WKY) rat and the maternally separated (MS) rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains. Conclusions: These data suggest that both early life stress (MS) and a genetic predisposition (WKY) to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS

Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin-6 on colonic function in Sprague–Dawley rats

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

A Distinct Profile of Tryptophan Metabolism along the Kynurenine Pathway Downstream of Toll-Like Receptor Activation in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS), a disorder of the brain-gut axis, is characterised by the absence of reliable biological markers. Tryptophan is an essential amino acid that serves as a precursor to serotonin but which can alternatively be metabolised along the kynurenine pathway leading to the production of other neuroactive agents. We previously reported an increased degradation of tryptophan along this immunoresponsive pathway in IBS. Recently, altered cytokine production following activation of specific members of the toll-like receptor (TLR) family (TLR1-9) has also been demonstrated in IBS. However, the relationship between TLR activation and kynurenine pathway activity in IBS is unknown. In this study, we investigated whether activation of specific TLRs elicits exaggerated kynurenine production in IBS patients compared to controls. Whole blood from IBS patients and healthy controls was cultured with a panel of nine different TLR agonists for 24 h. Cell culture supernatants were then analyzed for both tryptophan and kynurenine concentrations, as were plasma samples from both cohorts. IBS subjects had an elevated plasma kynurenine:tryptophan ratio compared to healthy controls. Furthermore, we demonstrated a differential downstream profile of kynurenine production subsequent to TLR activation in IBS patients compared to healthy controls. This profile included alterations at TLR1/2, TLR2, TLR3, TLR5, TLR7, and TLR8. Our data expands on our previous understanding of altered tryptophan metabolism in IBS and suggests that measurement of tryptophan metabolites downstream of TLR activation may ultimately find utility as components of a biomarker panel to aid gastroenterologists in the diagnosis of IBS. Furthermore, these studies implicate the modulation of TLRs as means through which aberrant tryptophan metabolism along the kynurenine pathway can be controlled, a novel potential therapeutic strategy in this and other disorders

A role for viral infections in Parkinson's etiology?

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.peer-reviewe

Anti-Viral Pattern Recognition Receptors as Therapeutic Targets

Pattern recognition receptors (PRRs) play a central role in the inflammation that ensues following microbial infection by their recognition of molecular patterns present in invading microorganisms but also following tissue damage by recognising molecules released during disease states. Such receptors are expressed in a variety of cells and in various compartments of these cells. PRR binding of molecular patterns results in an intracellular signalling cascade and the eventual activation of transcription factors and the release of cytokines, chemokines, and vasoactive molecules. PRRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. They are also key to reacting to infection and in stimulating the immune system when needed. Therefore, targeting PRRs offers a potential therapeutic approach for chronic inflammatory disease, infections and as vaccine adjuvants. In this review, the current knowledge on anti-viral PRRs and their signalling pathways is reviewed. Finally, compounds that target PRRs and that have been tested in clinical trials for chronic infections and as adjuvants in vaccine trials are discussed

The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review

α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson’s disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson’s disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions

Understanding the regulation of pattern recognition receptors in inflammatory diseases - a ‘nod’ in the right direction

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