Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.

First seen as a storage organ, the white adipose tissue (WAT) is now considered as an endocrine organ. WAT can produce an array of bioactive factors known as adipokines acting at physiological level and playing a vital role in energy metabolism as well as in immune response. The global effect of adipokines in metabolic activities is well established, but their impact on the physiology and the pathophysiology of the central nervous system (CNS) remains poorly defined. Adipokines are not only produced by the WAT but can also be expressed in the CNS where receptors for these factors are present. When produced in periphery and to affect the CNS, these factors may either cross the blood brain barrier (BBB) or modify the BBB physiology by acting on cells forming the BBB. Adipokines could regulate neuroinflammation and oxidative stress which are two major physiological processes involved in neurodegeneration and are associated with many chronic neurodegenerative diseases. In this review, we focus on four important adipokines (leptin, resistin, adiponectin, and TNFα) and one lipokine (lysophosphatidic acid—LPA) associated with autotaxin, its producing enzyme. Their potential effects on neurodegeneration and brain repair (neurogenesis) will be discussed. Understanding and regulating these adipokines could be an interesting lead to novel therapeutic strategy in order to counteract neurodegenerative disorders and/or promote brain repair.

No abstract

Sex steroid hormones are synthesized from cholesterol and exert pleiotropic effects notably in the central nervous system. Pioneering studies from Baulieu and colleagues have suggested that steroids are also locally-synthesized in the brain. Such steroids, called neurosteroids, can rapidly modulate neuronal excitability and functions, brain plasticity, and behavior. Accumulating data obtained on a wide variety of species demonstrate that neurosteroidogenesis is an evolutionary conserved feature across fish, birds, and mammals. In this review, we will first document neurosteroidogenesis and steroid signaling for estrogens, progestagens, and androgens in the brain of teleost fish, birds, and mammals. We will next consider the effects of sex steroids in homeostatic and regenerative neurogenesis, in neuroprotection, and in sexual behaviors. In a last part, we will discuss the transport of steroids and lipoproteins from the periphery within the brain (and vice-versa) and document their effects on the blood-brain barrier (BBB) permeability and on neuroprotection. We will emphasize the potential interaction between lipoproteins and sex steroids, addressing the beneficial effects of steroids and lipoproteins, particularly HDL-cholesterol, against the breakdown of the BBB reported to occur during brain ischemic stroke. We will consequently highlight the potential anti-inflammatory, anti-oxidant, and neuroprotective properties of sex steroid and lipoproteins, these latest improving cholesterol and steroid ester transport within the brain after insults.

Porphyromonas gingivalis is a key bacterium in chronic periodontitis, which is associated with several chronic inflammatory diseases. Lipopolysaccharides from P. gingivalis (Pg LPS) can activate multiple cell types via the production of pro-inflammatory cytokines. The receptors for Pg LPS have initially been reported as TLR2, contrasting with the well-studied TLR4 receptor for E. coli LPS; this observation remains controversial since synthetic Pg lipid A activates TLR4 but not TLR2. Despite this observation, the dogma of Pg LPS-mediated TLR2 activation remains the basis of many hypotheses and result interpretations. In the present work, we aimed at determining whether TLR4 or TLR2, or both, mediate Pg LPS pro-inflammatory activity using Pg LPS with different grades of purity, instead of synthetic lipid A from Pg LPS. Here we show that Pg LPS 1) acts exclusively through TLR4, and 2) are differently recognized by mouse and human TLR4 both in vitro and in vivo. Taken together, our results suggest that Pg LPS activity is mediated exclusively through TLR4 and only weakly induces proinflammatory cytokine secretion in mouse models. Caution should be taken when extrapolating data from mouse systems exposed to Pg or Pg LPS to humans.

BackgroundAdipose cells responsible for fat storage are the targets of reactive oxygen species (ROS) like H2O2 and pro-inflammatory agents including TNFα and LPS. Such mediators contribute to oxidative stress and alter inflammatory processes in adipose tissue, leading to insulin resistance during obesity. Thus, the identification of natural compounds such as plant polyphenols able to increase the antioxidant and anti-inflammatory capacity of the body is of high interest. We aimed to evaluate the biological properties of polyphenol-rich extracts from the medicinal plants A. borbonica, D. apetalum and G. mauritiana on preadipocytes exposed to H2O2, TNFα or LPS mediators.MethodsMedicinal plant extracts were analysed for their polyphenol contents by Folin-Ciocalteu and UPLC-ESI-MS methods as well as for their free radical-scavenging activities by DPPH and ORAC assays. To assess the ability of polyphenol-rich extracts to protect 3T3-L1 preadipocytes against H2O2, TNFα or LPS mediators, several parameters including cell viability (MTT and LDH assays), ROS production (DCFH-DA test), IL-6 and MCP-1 secretion (ELISA) were evaluated. Moreover, the expression of superoxide dismutase, catalase and NF-κB genes was explored (RT-QPCR).ResultsAll medicinal plants exhibited high levels of polyphenols with free radical-scavenging capacities. Flavonoids such as quercetin, kaempferol, epicatechin and procyanidins, and phenolic acids derived from caffeic acid including chlorogenic acid, were detected. Polyphenol-rich plant extracts did not exert a cytotoxic effect on preadipocytes but protected them against H2O2 anti-proliferative action. Importantly, they down-regulated ROS production and the secretion of IL-6 and MCP-1 pro-inflammatory markers induced by H2O2, TNFα and LPS mediators. Such a protective action was associated with an increase in superoxide dismutase antioxidant enzyme gene expression and a decrease in mRNA levels of NF-κB pro-inflammatory transcription factor.ConclusionThis study highlights that antioxidant strategies based on polyphenols derived from medicinal plants tested could contribute to regulate adipose tissue redox status and immune process, and thus participate to the improvement of obesity-related oxidative stress and inflammation.

International audienceLocalized tumor necrosis factor-α (TNFα) elevation has diverse effects in brain injury often attributed to signaling via TNFp55 or TNFp75 receptors. Both dentate granule cells and CA pyramidal cells express TNF receptors (TNFR) at low levels in a punctate pattern. Using a model to induce selective death of dentate granule cells (trimethyltin; 2 mg/kg, i.p.), neuronal apoptosis [terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ end labeling, active caspase 3 (AC3)] was accompanied by amoeboid microglia and elevated TNFα mRNA levels. TNFp55R (55 kDa type-1 TNFR) and TNFp75R (75 kDa type-2 TNFR) immunoreactivity in AC3+ neurons displayed a pattern suggestive of receptor internalization and a temporal sequence of expression of TNFp55R followed by TNFp75R associated with the progression of apoptosis. A distinct ramified microglia response occurred around CA1 neurons and healthy dentate neurons that displayed an increase in the normal punctate pattern of TNFRs. Neuronal damage was decreased with i.c.v. injection of TNFα antibody and in TNFp55R−/−p75R−/− mice that showed higher constitutive mRNA levels for interleukin (IL-1α), macrophage inflammatory protein 1-α (MIP-1α), TNFα, transforming growth factor β1, Fas, and TNFRSF6-assoicated via death domain (FADD). TNFp75R−/− mice showed exacerbated injury and elevated mRNA levels for IL-1α, MIP-1α, and TNFα. In TNFp55R−/− mice, constitutive mRNA levels for TNFα, IL-6, caspase 8, FADD, and Fas-associated phosphatase were higher; IL-1α, MIP-1α, and transforming growth factor β1 lower. The mice displayed exacerbated neuronal death, delayed microglia response, increased FADD and TNFp75R mRNA levels, and co-expression of TNFp75R in AC3+ neurons. The data demonstrate TNFR-mediated apoptotic death of dentate granule neurons utilizing both TNFRs and suggest a TNFp75R-mediated apoptosis in the absence of normal TNFp55R activity

In addition to the well-known role of adipose tissue in energy metabolism, it has recently been demonstrated that this tissue can secrete a large array of molecules, including inflammatory cytokines. Furthermore, recent studies suggest that adipose cells can behave as immune cells. Therefore, the aim of this study was to determine the presence of the two most prominent 'pattern recognition receptors' for bacterial and fungal cell wall components, TLR2 and TLR4 on human adipose cells, as well as to assess their functionality. We demonstrated that TLR2 and TLR4 were expressed at relatively high levels (compared to a monocyte cell line) on the surface of human adipose cells. Stimulation of human adipocytes with lipopolysaccharide (LPS), or with lipoteichoic acid (LTA), two specific ligands of TLR4 and TLR2, respectively, induced a strong increase in TNFalpha production. The specificity of the response was demonstrated by the use of anti-TLR4 and anti-TLR2 blocking antibodies, which were able to decrease LPS- or LTA-induced TNFalpha secretion. Thus, it is clear that these receptors are functional in human adipocytes. This study adds weight to the argument that human fat tissue plays a potential role in innate immunity.