Dual functionality of interleukin-1 family cytokines: implications for anti-interleukin-1 therapy

Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine-expressing or cytokine-responsive cells. Interleukin-1 (IL-1) family cytokines are key pro-inflammatory mediators, and blockade of the IL-1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL-1 extracellular actions. Here we review evidence that suggests IL-1 family members have dual functionality. Several IL-1 family members have been detected inside the nuclei of IL-1-expressing or IL-1-responsive cells, and intranuclear IL-1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL-1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL-1 family members represent a new and potentially important area of IL-1 biology and may have implications for the future development of anti-IL-1 therapies

Nuclear retention of IL-1 alpha by necrotic cells: A mechanism to dampen sterile inflammation

Sterile inflammation is a host response to tissue injury that is mediated by damage-associated molecular patterns (DAMPs) released from dead cells. Sterile inflammation worsens damage in a number of injury paradigms. The pro-inflammatory cytokine interleukin-1α (IL-1α) is reported to be a DAMP released from dead cells, and is known to exacerbate brain injury caused by stroke. In the brain, IL-1α is produced by microglia, the resident brain macrophages. We found that IL-1α is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1α to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygen-glucose deprivation (OGD) died via necrosis. Under these conditions, microglia expressing nuclear IL-1α released significantly less IL-1α than microglia with predominantly cytosolic IL-1α. The remaining IL-1α was immobilised in the nuclei of the dead cells. Thus, nuclear retention of IL-1α may serve to limit inflammation following cell death

Moving pathogen genomics out of the lab and into the clinic: what will it take?

Pathogen genomic analysis is a potentially transformative new approach to the clinical and public-health management of infectious diseases. Health systems investing in this technology will need to build infrastructure and develop policies that ensure genomic information can be generated, shared and acted upon in a timely manner

Prenatal Inflammation-Induced Hypoferremia Alters Dopamine Function in the Adult Offspring in Rat: Relevance for Schizophrenia

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans

Cycloadditions to 1-azetines and 1-azetin-4-ones

1-Azetines (1) have until recently been unknown. Prepared for the first time in 1967, they since have met with little interest. The azetine system is a thermolabile one, as to be expected from a strained four-membered ring incorporating a C=N bond.1,3-Dipolar cycloadditions and [4+2] cycloadditions to the C=N bond of 1-azetines would yield bi-cyclic systems of related structure to the beta-lactam nucleus of beta-lactam antibitics.Thus, three 1-azetine systems (2-4) were prepared by alkylation of their precursor azetidinones and thioazetidinones.The ability of these systems to enter into cycloaddition reactions with a variety of 1,3-dipoles and dienes was investigated.Nitrile oxides (5) and nitrile ylides (7) were found to add smoothly to the 1-azetine systems to yield the bicyclic adducts (6) and (8) respectively.Nitrile imines (9) also add to 1-azetines in a similar fashion to yield the bi-cyclic adduct (10). In some cases, however, these adducts were found to undergo a rearrangement reaction to the bi-cyclic triazoles (11).Attempted [4+2] cycloadditions using electron rich and electron deficient dienes to 1-azetines were unsuccesful.In an extension of this work, addition of 1,3-dipoles to l-azetin-4-one (12) was also attempted, in a bid to establish a new route to the highly sought after beta-lactam antibiotics. Unfortunately, azetinone (12) was found to be unreactive towards both nitrile oxides and imines.This lack of reactivity of azetinone (12) is believed to be due to steric hinderance by the geminal ¿-butyl groups. Hence, several attempts were made to synthesise an azetinone species free of these constraints were made. This work remains incomplete, and is expected to attract further research.Finally, some work was done to investigate the effectiveness of aryl iminophosphoranes (13) as precursors to a variety of heterocyclic systems, including 1,3-benzoxazoles, 1,4- benzoxazines, and benzodiazepines

Role of neuroinflammation in the emotional and cognitive alterations displayed by animal models of obesity

Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients

Interactions between state pension and long-term care reforms: an overview

In April 2016 major reforms to state pensions and long-term care will be implemented in Great Britain and England respectively. Their combined effects have received little attention despite interactions between the two systems. The long-term effects of both sets of reforms will depend on how details of the systems are set in the intervening years, and on how policies in other parts of the welfare system evolve. We will investigate the long-term impacts of alternative ways in which current pensions and long-term care financing reforms may evolve over the next 40 years to ensure that that there is widespread appreciation of the implications of any changes which may have significant long-term effects