Toll-Like Receptor 4 on Nonhematopoietic Cells Sustains CNS Inflammation during Endotoxemia, Independent of Systemic Cytokines (original) (raw)
Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation
Proceedings of the National Academy of Sciences of the United States of America, 2013
Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immuneadrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPAaxis activation mediated by LPS were found in Mx1 Cre+ -MyD88 fl/fl mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.
Morphine Preconditioning Protects Against LPS-Induced Neuroinflammation and Memory Deficit
Journal of Molecular Neuroscience, 2012
Recent studies show that morphine possesses protective preconditioning effects in different ischemia/reperfusion models. However, there is very little information about the antineuroinflammatory role of morphine and its protective effect against memory deficit. In the present study, we evaluated the role of morphine preconditioning in a model of mild neuroinflammation induced by intraperitoneal lipopolysaccharide (LPS) injection (1 mg/kg). Rats were trained on passive avoidance apparatus and challenged with LPS 20 h later. Four hours after LPS, rats were subjected to passive avoidance testing and then for the assessments of inflammatory and apoptotic cell death mediators in the hippocampus. LPS significantly increased the nuclear NF-κB and expression of COX-2, IL-1β, and TNF-α, augmented the activity of caspase-3 and PARP cleavage, and in parallel shortened the latencies to enter the dark compartment. Although morphine injection in a noninflammatory context was able to induce a neuroinflammatory response and memory loss, morphine preconditioning at the dose of 4 mg/kg significantly prevented the LPS-induced neuroinflammation and memory deficit. Morphine preconditioning was abolished by naloxone and, therefore, is dependent on opioid receptors. These results suggest that acute morphine injection, in spite of the induction of a neuroinflammatory response and amnesia per se, exerts an antineuroinflammatory role and protects from cell death and memory deficit in an inflammatory context.
Journal of Neuroinflammation, 2014
Background: Genetic and environmental factors are critical elements influencing the etiology of major depression. It is now accepted that neuroinflammatory processes play a major role in neuropsychological disorders. Neuroinflammation results from the dysregulation of the synthesis and/or release of pro-and anti-inflammatory cytokines with central or peripheral origin after various insults. Systemic bacterial lipopolysaccharide (LPS) challenge is commonly used to study inflammation-induced depressive-like behaviors in rodents. In the present study, we investigated immune-to-brain communication in mice by examining the effects of peripheral LPS injection on neuroinflammation encompassing cytokine and chemokine production, microglia and central nervous system (CNS)-associated phagocyte activation, immune cell infiltration and serotonergic neuronal function. Methods: LPS was administered to C57BL/6 J mice by intraperitoneal injection; brains were collected and proinflammatory cytokine mRNA and proteins were measured. To examine the relative contribution of the different populations of brain immune cells to the occurrence of neuroinflammation after acute systemic inflammation, we precisely characterized them by flow cytometry, studied changes in their proportions and level of activation, and measured the amount of cytokines they released by Cytometric Bead Array™ after cell sorting and ex vivo culture. Because of the central role that the chemokine CCL2 seems to play in our paradigm, we studied the effect of CCL2 on the activity of serotonergic neurons of the raphe nucleus using electrophysiological recordings.
A20 deficiency causes spontaneous neuroinflammation in mice
Journal of Neuroinflammation, 2014
Background: A20 (TNFAIP3) is a pleiotropic NFκB-dependent gene that terminates NFκB activation in response to inflammatory stimuli. The potent anti-inflammatory properties of A20 are well characterized in several organs. However, little is known about its role in the brain. In this study, we investigated the brain phenotype of A20 heterozygous (HT) and knockout (KO) mice. Methods: The inflammatory status of A20 wild type (WT), HT and KO brain was determined by immunostaining, quantitative PCR, and Western blot analysis. Cytokines secretion was evaluated by ELISA. Quantitative results were statistically analyzed by ANOVA followed by a post-hoc test.
Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction
Journal of Neurochemistry, 2011
Neurological diseases account for approximately 30% of the total disease burden in Europe and neurodegenerative diseases account for a significant proportion of these (Olesen and Leonardi 2003). The neuromodulation system operated by adenosine has received an increasing attention as a potential novel target to manage neurodegenerative conditions, in view of its combined neuronal, glial and vascular effects (reviewed in Fredholm et al. 2005). This is best exemplified by the current development (phase IIb) of adenosine A 2A receptor (A2AR) antagonists as anti-Parkin-
Translational Stroke Research, 2013
The choroid plexus is the site of the blood-cerebrospinal fluid (CSF) barrier (BCSFB) and has also been considered as a possible route for peripheral immune signals and cells to transfer to the central nervous system. Infection/ inflammation stimulates innate and subsequent adaptive immune responses via Toll-like receptors (TLRs). In this study, we have investigated the mRNA expression of TLRs, cytokines, and tight junction proteins in the choroid plexus in the immature brain after systemic inflammation, as well as accumulation of immune cells into the CSF. Specific ligands for TLR-1/2, TLR-3, and TLR-4 were administered to postnatal day 8 mice and mRNA expression for the targeted genes was examined in the choroid plexus. We found that mRNA for all four TLRs was detected in the choroid plexus under control conditions. Following immune stimulation, expression of all the TLRs was upregulated by their respective ligands, except for TLR-4 mRNA, which was downregulated by Pam 3 CSK 4 (PAM; a TLR-1/2 ligand). In addition, we investigated BCSFB regulation after TLR stimulation and found that TLR-1/2 and TLR-4 activation was associated with changes in mRNA expression of the tight junction protein occludin in the choroid plexus. PAM induced choroid plexus transcription of TNF-α and resulted in the most dramatic increase in numbers of white blood cells in the CSF. The data suggest a possible mechanism whereby systemic inflammation stimulates TLRs in the choroid plexus, which may lead to disturbances in choroid plexus barrier function, as well as infiltration of immune cells through the plexus.
Frontiers in cellular neuroscience, 2014
We show here that a mild sterile inflammation induced by the endotoxin lipopolysaccharide (LPS), in a neuron/astrocyte/microglial cortical network, modulates neuronal excitability and can initiate long-duration burst events resembling epileptiform seizures, a recognized feature of various central nervous neurodegenerative, neurological and acute systemic diseases associated with neuroinflammation. To study this action, we simultaneously analyzed the reverberating bursting activity of a hundred neurons by using in vitro multi-electrode array methods. ∼5 h after LPS application, we observed a net increase in the average number of spikes elicited in engaged cells and within each burst, but no changes neither in spike waveforms nor in burst rate. This effect was characterized by a slow, twofold exponential increase of the burst duration and the appearance of rarely occurring long burst events that were never seen during control recordings. These changes and the time-course of microglia-...
Esophageal cancer-related gene-4 (ECRG4) interactions with the innate immunity receptor complex
Inflammation Research
Objective and design The human c2orf40 gene encodes a tumor suppressor gene called esophageal cancer-related gene-4 (ECRG4) with pro- and anti-inflammatory activities that depend on cell surface processing. Here, we investigated its physical and functional association with the innate immunity receptor complex. Methods Interactions between ECRG4 and the innate immunity receptor complex were assessed by flow cytometry, immunohistochemistry, confocal microscopy, and co-immunoprecipitation. Phage display was used for ligand targeting to cells that overexpress the TLR4–MD2–CD14. Results Immunoprecipitation and immunohistochemical studies demonstrate a physical interaction between ECRG4 and TLR4–MD2–CD14 on human granulocytes. Flow cytometry shows ECRG4 on the cell surface of a subset of CD14+ and CD16+ leukocytes. In a cohort of trauma patients, the C-terminal 16 amino acid domain of ECRG4 (ECRG4133–148) appears to be processed and shed, presumably at a thrombin-like consensus sequence. ...
PloS one, 2014
Blood-brain barrier (BBB) impairment in systemic inflammation leads to neuroinflammation. Several factors including cytokines, chemokines and signal transduction molecules are implicated in BBB dysfunction in response to systemic inflammation. Here, we have adopted a novel in vivo technique; namely, cerebral open flow microperfusion (cOFM), to perform time-dependent cytokine analysis (TNF-alpha, IL-6 and IL-10) in the frontal cortex of the rat brain in response to a single peripheral administration of lipopolysaccharide (LPS). In parallel, we monitored BBB function using sodium fluorescein as low molecular weight reporter in the cOFM sample. In response to the systemic LPS administration, we observed a rapid increase of TNF-alpha in the serum and brain, which coincides with the BBB disruption. Brain IL-6 and IL-10 synthesis was delayed by approximately 1 h. Our data demonstrate that cOFM can be used to monitor changes in brain cytokine levels and BBB disruption in a rat sepsis model.
ASN NEURO, 2009
MyD88 KO (knockout) mice are exquisitely sensitive to CNS (central nervous system) infection with Staphylococcus aureus, a common aetiological agent of brain abscess, exhibiting global defects in innate immunity and exacerbated tissue damage. However, since brain abscesses are typified by the involvement of both activated CNS-resident and infiltrating immune cells, in our previous studies it has been impossible to determine the relative contribution of MyD88-dependent signalling in the CNS compared with the peripheral immune cell compartments. In the present study we addressed this by examining the course of S. aureus infection in MyD88 bone marrow chimaera mice. Interestingly, chimaeras where MyD88 was present in the CNS, but not bone marrow-derived cells, mounted proinflammatory mediator expression profiles and neutrophil recruitment equivalent to or exceeding that detected in WT (wild-type) mice. These results implicate CNS MyD88 as essential in eliciting the initial wave of inflammation during the acute response to parenchymal infection. Microarray analysis of infected MyD88 KO compared with WT mice revealed a preponderance of differentially regulated genes involved in apoptotic pathways, suggesting that the extensive tissue damage characteristic of brain abscesses from MyD88 KO mice could result from dysregulated apoptosis. Collectively, the findings of the present study highlight a novel mechanism for CNS-resident cells in initiating a protective innate immune response in the infected brain and, in the absence of MyD88 in this compartment, immunity is compromised.
Molecular medicine (Cambridge, Mass.), 2012
Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neur...
PLoS ONE, 2013
It is increasingly clear that systemic inflammation has both adaptive and deleterious effects on the brain. However, detailed comparisons of brain effects of systemic challenges with different pro-inflammatory cytokines are lacking. In the present study, we challenged female C57BL/6 mice intraperitoneally with LPS (100 µg/kg), IL-1β (15 or 50 µg/kg), TNF-α (50 or 250 µg/kg) or IL-6 (50 or 125 µg/kg). We investigated effects on core body temperature, open field activity and plasma levels of inflammatory markers at 2 hours post injection. We also examined levels of hepatic, hypothalamic and hippocampal inflammatory cytokine transcripts. Hypothermia and locomotor hypoactivity were induced by LPS>IL-1β>TNF-α>>IL-6. Systemic LPS, IL-1β and TNF-α challenges induced robust and broadly similar systemic and central inflammation compared to IL-6, which showed limited effects, but did induce a hepatic acute phase response. Important exceptions included IFNβ, which could only be induced by LPS. Systemic IL-1β could not induce significant blood TNF-α, but induced CNS TNF-α mRNA, while systemic TNF-α could induce IL-1β in blood and brain. Differences between IL-1β and TNF-α-induced hippocampal profiles, specifically for IL-6 and CXCL1 prompted a temporal analysis of systemic and central responses at 1, 2, 4, 8 and 24 hours, which revealed that IL-1β and TNF-α both induced the chemokines CXCL1 and CCL2 but only IL-1β induced the pentraxin PTX3. Expression of COX-2, CXCL1 and CCL2, with nuclear localisation of the p65 subunit of NFκB, in the cerebrovasculature was demonstrated by immunohistochemistry. Furthermore, we used cFOS immunohistochemistry to show that LPS, IL-1β and to a lesser degree, TNF-α activated the central nucleus of the amygdala. Given the increasing attention in the clinical literautre on correlating specific systemic inflammatory mediators with neurological or neuropsychiatric conditions and complications, these data will provide a useful resource on the likely CNS inflammatory profiles resulting from systemic elevation of particular cytokines.
Regulation of Toll-like receptor 1 and -2 in neonatal mice brains after hypoxia-ischemia
Journal of Neuroinflammation, 2011
Background: Hypoxic-ischemic (HI) brain injury remains a major problem in newborns, resulting in increased risk of neurological disorders. Neonatal HI triggers a broad inflammatory reaction in the brain, including activation of the innate immune system. Toll-like receptors (TLRs), which are key components of the innate immune system, are believed to play a role in adult cerebral ischemic injury. The expression of TLRs in the neonatal brain and their regulation after HI is unknown. Methods: Wild type C57BL/6, TLR 1 knockout (KO) and TLR 2 KO mice were subjected to HI at postnatal day 9 and sacrificed 30 min, 6 h, 24 h or 5 days after HI. TLR mRNA expression was determined by RT-qPCR and protein and cell type localisation by immunohistochemistry (IHC). To evaluate brain injury, infarct volume was measured in the injured hemisphere.
PLOS ONE, 2016
Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGFβ were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.
Journal of Neurochemistry, 2007
New neurons are continuously generated in hippocampal subgranular zone throughout life, and the amount of neurogenesis is suggested to be correlated with the hippocampusdependent function. Several extrinsic stimuli are known to modulate the neurogenesis process. Among them, physical exercise has advantageous effects on neurogenesis and brain function, while inflammation shows the opposite. Herein we showed that a moderate running exercise successfully restored the peripheral lipopolysaccharide (LPS)-impaired neurogenesis in the dentate area. LPS treatment obstructed neuronal differentiation, but not proliferation. Exercise training facilitated both the proliferation of the neural stem cells and their differentiation into neurons. Interestingly, exercise replenished the LPS-reduced levels of brain-derived neurotrophic factor and its receptor, TrkB, and rescued the LPSdisturbed performance in water maze; while the LPS-elicited up-regulation of tumor necrosis factor-alpha and interleukin-1b remained unaltered. In conclusion, our findings suggest that running exercise effectively ameliorates the LPS-disturbed hippocampal neurogenesis and learning and memory performance. Such advantageous effects of running exercise are not due to the alteration of inflammatory response, but possibly by the restoring the LPS-lessened brain-derived neurotrophic factor signaling pathway.
Neurogastroenterology & Motility, 2012
Background Early murine endotoxin-induced ileus at 6 h is exclusively mediated by non-hemopoietic TLR4/ MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus. Methods CSF-1)/) , TLR4 non-chimera and TLR4 chimera mice were single-shot intraperitoneal injected with ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4 WT mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB). Key Results Hemopoietic TLR4 signaling independently mediated UP-LPS-induced ileus at 24 h, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and non-hemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS dose dependent, but exogenous rmIL-6 did not spark off a self-perpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels. Conclusions & Inferences A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with nonhemopoietic cells thereby prolonging ileus and fueling intestinal inflammation. Importantly, IL-6 signaling via IL-6R/gp130 drives late ileus, yet it did not regulate mortality in endotoxic shock.
Potential Mechanisms Underlying Inflammation-Enhanced Aminoglycoside-Induced Cochleotoxicity
Frontiers in Cellular Neuroscience
Aminoglycoside antibiotics remain widely used for urgent clinical treatment of lifethreatening infections, despite the well-recognized risk of permanent hearing loss, i.e., cochleotoxicity. Recent studies show that aminoglycoside-induced cochleotoxicity is exacerbated by bacteriogenic-induced inflammation. This implies that those with severe bacterial infections (that induce systemic inflammation), and are treated with bactericidal aminoglycosides are at greater risk of drug-induced hearing loss than previously recognized. Incorporating this novel comorbid factor into cochleotoxicity risk prediction models will better predict which individuals are more predisposed to druginduced hearing loss. Here, we review the cellular and/or signaling mechanisms by which host-mediated inflammatory responses to infection could enhance the trafficking of systemically administered aminoglycosides into the cochlea to enhance the degree of cochleotoxicity over that in healthy preclinical models. Once verified, these mechanisms will be potential targets for novel pharmacotherapeutics that reduce the risk of druginduced hearing loss (and acute kidney damage) without compromising the life-saving bactericidal efficacy of aminoglycosides.
PloS one, 2016
Systemic infection can initiate or exacerbate central nervous system (CNS) pathology, even in the absence of overt invasion of bacteria into the CNS. Recent epidemiological studies have demonstrated that human survivors of sepsis have an increased risk of long-term neurocognitive decline. There is thus a need for improved understanding of the physiological mechanisms whereby acute sepsis affects the CNS. In particular, MyD88-dependent activation of brain microvascular endothelial cells and a resulting loss of blood-brain barrier integrity have been proposed to play an important role in the effects of systemic inflammation on the CNS. Signaling through the vagus nerve has also been considered to be an important component of CNS responses to systemic infection. Here, we demonstrate that blood-brain barrier permeabilization and hippocampal transcriptional responses during polymicrobial sepsis occur even in the absence of MyD88-dependent signaling in cerebrovascular endothelial cells. W...
PLOS ONE
Despite the increased risks of cancers and cardiovascular related diseases, tobacco smoking continues to be prevalent in the population due largely in part to the addictive nature of nicotine. Nicotine vaccines are an attractive alternative to the current smoking cessation options but have yet to be successful enough in clinical trials to reach the market due to a lack of neutralizing antibodies and inconsistent results. Using AFPL1 derived from the Cuban meningococcal vaccine as an adjuvant, we have previously published promising results with an intranasally administered nicotine vaccine. In order to examine the immunogenicity and safety of this vaccine in mice we set up a pilot trial administering the vaccine either intranasally, intramuscularly or utilizing both routes simultaneously and evaluated immune responses and clinical symptoms throughout the duration of the vaccination protocol and post-mortem. These data further demonstrate the ability of the AFPL1 nicotine conjugate vaccine to be a safe and potential candidate for clinical use.
Repeat-Dose Toxicity Study Using the AFPL1-Conjugate Nicotine Vaccine in Male Sprague Dawley Rats
Pharmaceutics
Tobacco smoking is the cause of 20% of Canadian deaths per year. Nicotine vaccines present a promising alternative to traditional smoking cessation products, but to date, no vaccine has been able to move through all phases of clinical trials. We have previously demonstrated that the AFPL1-conjugate nicotine vaccine does not induce systemic or immunotoxicity in a mouse model and that a heterologous vaccination approach is more advantageous than the homologous routes to inducing mucosal and systemic anti-nicotine antibodies. The purpose of this study was to confirm the safety profile of the vaccine in a repeat-dose toxicity study. The heterologous vaccination strategy was again used, and Sprague Dawley rats were administered a dose five times greater than in our previous studies. Physiological conditions, food and water consumption, body temperature, injection site inflammation, relative weights of organs, histopathology, and blood chemistry and hematology were evaluated during the co...
Central mediators involved in the febrile response: effect of antipyretic drugs
Temperature, 2015
Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1b, tumor necrosis factor-a, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions.
Scientific reports, 2017
Physiologically, lipopolysaccharide (LPS) is present in the bloodstream and can be bound to several proteins for its transport (i.e.) LPS binding protein (LBP) and plasma lipoproteins). LPS receptors CD14 and TLR-4 are constitutively expressed in the Central Nervous System (CNS). To our knowledge, LPS infiltration in CNS has not been clearly demonstrated. A naturalistic experiment with healthy rats was performed to investigate whether LPS is present with its receptors in brain. Immunofluorescences showed that lipid A and core LPS were present in circumventricular organs, choroid plexus, meningeal cells, astrocytes, tanycytes and endothelial cells. Co-localization of LPS regions with CD14/TLR-4 was found. The role of lipoprotein receptors (SR-BI, ApoER2 and LDLr) in the brain as targets for a LPS transport mechanism by plasma apolipoproteins (i.e. ApoAI) was studied. Co-localization of LPS regions with these lipoproteins markers was observed. Our results suggest that LPS infiltrates ...
Brain sciences, 2015
Citrus polymethoxylated flavones (PMFs) have recently been shown to suppress inflammation in peripheral tissues. In the present study, we investigated the effects of 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), one of the PMFs, on inflammation in the brain in vivo using mice injected intrahippocampally with lipopolysaccharide (LPS). We demonstrated that subcutaneously injected HMF suppressed: (1) LPS-induced losses in body weight; (2) LPS-induced microglial activation in the hippocampus; and (3) LPS-induced interleukin-1β mRNA expression in the hippocampus. These results suggest that HMF has the ability to reduce neuroinflammation in the brain.
2021
Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control. The peripheral administration of low-dose lipopolysaccharide (LPS) at 50 μg/kg generated fever in wild-type (WT) mice, whereas it caused hypothermia in TRPM8 knockout (KO) animals. LPS-induced sickness responses such as decrease in body weight, and food and water intake were not different between WT and TRPM8 KO mice. TRPM8 KO mice exhibited more severe hypothermia and lower locomotor activity following the peripheral administration of high-dose LPS at 5 mg/kg compared with WT ones. An intracerebroventricular (i.c.v.) injection of either LPS at 3.6 μg/kg or interleukin-1β at 400 ng/kg elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals. The peripheral adminis...
Cell Death and Differentiation, 2013
In CNS, glucocorticoids (GCs) activate both GC receptor (GR) and mineralocorticoid receptor (MR), whereas GR is widely expressed, the expression of MR is restricted. However, both are present in the microglia, the resident macrophages of the brain and their activation can lead to pro-or anti-inflammatory effects. We have therefore addressed the specific functions of GR in microglia. In mice lacking GR in macrophages/microglia and in the absence of modifications in MR expression, intraparenchymal injection of lipopolysaccharide (LPS) activating Toll-like receptor 4 signaling pathway resulted in exacerbated cellular lesion, neuronal and axonal damage. Global inhibition of GR by RU486 pre-treatment revealed that microglial GR is the principal mediator preventing neuronal degeneration triggered by lipopolysaccharide (LPS) and contributes with GRs of other cell types to the protection of non-neuronal cells. In vivo and in vitro data show GR functions in microglial differentiation, proliferation and motility. Interestingly, microglial GR also abolishes the LPS-induced delayed outward rectifier currents by downregulating Kv1.3 expression known to control microglia proliferation and oxygen radical production. Analysis of GR transcriptional function revealed its powerful negative control of pro-inflammatory effectors as well as upstream inflammatory activators. Finally, we analyzed the role of GR in chronic unpredictable mild stress and aging, both known to prime or sensitize microglia in vivo. We found that microglial GR suppresses rather than mediates the deleterious effects of stress or aging on neuronal survival. Overall, the results show that microglial GR acts on several key processes limiting pro-inflammatory actions of activated microglia.
Circumventricular Organs and Parasite Neurotropism: Neglected Gates to the Brain?
Frontiers in Immunology, 2018
Circumventricular organs (CVOs), neural structures located around the third and fourth ventricles, harbor, similarly to the choroid plexus, vessels devoid of a blood-brain barrier (BBB). This enables them to sense immune-stimulatory molecules in the blood circulation, but may also increase chances of exposure to microbes. In spite of this, attacks to CVOs by microbes are rarely described. It is here highlighted that CVOs and choroid plexus can be infected by pathogens circulating in the bloodstream, providing a route for brain penetration, as shown by infections with the parasites Trypanosoma brucei. Immune responses elicited by pathogens or systemic infections in the choroid plexus and CVOs are briefly outlined. From the choroid plexus trypanosomes can seed into the ventricles and initiate accelerated infiltration of T cells and parasites in periventricular areas. The highly motile trypanosomes may also enter the brain parenchyma from the median eminence, a CVO located at the base of the third ventricle, by crossing the border into the BBB-protected hypothalamic arcuate nuclei. A gate may, thus, be provided for trypanosomes to move into brain areas connected to networks of regulation of circadian rhythms and sleep-wakefulness, to which other CVOs are also connected. Functional imbalances in these networks characterize human African trypanosomiasis, also called sleeping sickness. They are distinct from the sickness response to bacterial infections, but can occur in common neuropsychiatric diseases. Altogether the findings lead to the question: does the neglect in reporting microbe attacks to CVOs reflect lack of awareness in investigations or of gate-opening capability by microbes?
Toxicology, 2022
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New means to assess neonatal inflammatory brain injury
Journal of neuroinflammation, 2015
Preterm infants are especially vulnerable to infection-induced white matter injury, associated with cerebral palsy, cognitive and psychomotor impairment, and other adverse neurological outcomes. The etiology of such lesions is complex and multifactorial. Furthermore, timing and length of exposure to infection also influence neurodevelopmental outcomes. Different mechanisms have been posited to mediate the observed brain injury including microglial activation followed by subsequent release of pro-inflammatory species, glutamate-induced excitotoxicity, and vulnerability of developing oligodendrocytes to cerebral insults. The prevalence of such neurological impairments requires an urgent need for early detection and effective neuroprotective strategies. Accordingly, noninvasive methods of monitoring disease progression and therapy effectiveness are essential. While diagnostic tools using biomarkers from bodily fluids may provide useful information regarding potential risks of developin...
Nutrients, 2021
It has been previously demonstrated that KEKS food containing exogenous ketogenic supplement ketone salt (KS) and ketone ester (KE) decreased the lipopolysaccharide (LPS)-generated increase in SWD (spike-wave discharge) number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, likely through ketosis. KEKS-supplemented food-generated ketosis may increase adenosine levels, and may thus modulate both neuroinflammatory processes and epileptic activity through adenosine receptors (such as A1Rs and A2ARs). To determine whether these adenosine receptors are able to modify the KEKS food-generated alleviating effect on LPS-evoked increases in SWD number, an antagonist of A1R DPCPX (1,3-dipropyl-8-cyclopentylxanthine; 0.2 mg/kg) with LPS (50 µg/kg) and an antagonist of A2AR SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; 0.5 mg/kg) with LPS were co-injected intraperitoneally (i.p.) on the ninth day of KEKS food administration, and their influence...
Differential distribution and activation of microglia in the brain of male C57BL/6J mice
Brain Structure and Function, 2012
Upon certain stimuli, microglia undergo different degrees of transformation in order to maintain homeostasis of the CNS. However, chronic microglia activation has been suggested to play an active role in the pathogenesis of neurodegenerative diseases. The density of microglia and the degree of microglia activation vary among brain regions; such differences may underlie the brain region-specific characteristics of neurodegenerative diseases. In this study, we aim to characterize the temporal and spatial profiles of microglia activation induced by peripheral inflammation in male C57BL/6J mice. Our results showed that, on average, microglia densities were highest in the cortex, followed by the limbic area, basal nuclei, diencephalon, brainstem and cerebellum. Among the 22 examined brain nuclei/regions, the substantia nigra had the highest microglia density. Microglia morphological changes were evident within 3 h after a single intraperitoneal lipopolysaccharides injection, with the highest degree of changes also in the substantia nigra. The lipopolysaccharide-induced microglia activation, determined by maximal cell size, was positively correlated with density of microglia and levels of TNFa receptor 1; it was not correlated with original microglia cell size or integrity of blood-brain barrier. The differential response of microglia also cannot be explained by different types of neurotransmitters. Our works suggest that the high density of microglia and the high levels of TNFa receptor 1 in the substantia nigra make this brain region the most susceptible area to systemic immunological insults.
2021
The anti-inflammatory cytokine interleukin-37 (IL-37) is a member of the IL-1 family but not expressed in mice. We used a human IL-37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Those studies demonstrate an immune-modulatory role of IL-37 which can be characterized as an important suppressor of innate immunity. We investigated the functions of IL-37 in the CNS and explored the effects of IL-37 on neuronal architecture and function, microglia phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. Reduced spine density, activated microglia phenotype and impaired long-term potentiation (LTP) were observed in wild-type mice after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer’s disease (APP/PS1) to investigate the anti-inflammatory properties of IL-3...
Choroid plexus and the blood–cerebrospinal fluid barrier in disease
Fluids and Barriers of the CNS, 2020
The choroid plexus (CP) forming the blood–cerebrospinal fluid (B-CSF) barrier is among the least studied structures of the central nervous system (CNS) despite its clinical importance. The CP is an epithelio-endothelial convolute comprising a highly vascularized stroma with fenestrated capillaries and a continuous lining of epithelial cells joined by apical tight junctions (TJs) that are crucial in forming the B-CSF barrier. Integrity of the CP is critical for maintaining brain homeostasis and B-CSF barrier permeability. Recent experimental and clinical research has uncovered the significance of the CP in the pathophysiology of various diseases affecting the CNS. The CP is involved in penetration of various pathogens into the CNS, as well as the development of neurodegenerative (e.g., Alzheimer´s disease) and autoimmune diseases (e.g., multiple sclerosis). Moreover, the CP was shown to be important for restoring brain homeostasis following stroke and trauma. In addition, new diagnos...
TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease
Frontiers in Immunology, 2020
Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.
Effects of Intestinal Microbiota on Brain Development in Humanized Gnotobiotic Mice
Scientific reports, 2018
Poor growth in the Neonatal Intensive Care Unit is associated with an increased risk for poor neurodevelopmental outcomes for preterm infants, however the mechanism is unclear. The microbiome has increasingly been recognized as a modifiable environmental factor to influence host development. Here we explore the hypothesis that the microbiome influences both growth phenotype and brain development. A germ free mouse transfaunation model was used to examine the effects of preterm infant microbiotas known to induce either high growth or low growth phenotypes on postnatal brain development. The microbiome which induced the low growth phenotype was associated with decreases in the neuronal markers NeuN and neurofilament-L as well as the myelination marker MBP when compared to the microbiome associated with the high growth phenotype. Additionally, poor growth phenotype-associated microbiota was associated with increased neuroinflammation marked by increased Nos1, as well as alteration in I...
Molecular Neurobiology, 2020
Traumatic brain injury (TBI) induces inflammatory responses through microglial activation and polarization towards a more inflammatory state that contributes to the deleterious secondary brain injury. Glia maturation factor (GMF) is a pro-inflammatory protein that is responsible for neuroinflammation following insult to the brain, such as in TBI. We hypothesized that the absence of GMF in GMF-knockout (GMF-KO) mice would regulate microglial activation state and the M1/M2 phenotypes following TBI. We used the weight drop model of TBI in C57BL/6 mice wild-type (WT) and GMF-KO mice. Immunofluorescence staining, Western blot, and ELISA assays were performed to confirm TBI-induced histopathological and neuroinflammatory changes. Behavioral analysis was done to check motor coordination ability and cognitive function. We demonstrated that the deletion of GMF in GMF-KO mice significantly limited lesion volume, attenuated neuronal loss, inhibited gliosis, and activated microglia adopted predominantly anti-inflammatory (M2) phenotypes. Using an ELISA method, we found a gradual decrease in pro-inflammatory cytokines (TNF-α and IL-6) and upregulation of anti-inflammatory cytokines (IL-4 and IL-10) in GMF-KO mice compared with WT mice, thus, promoting the transition of microglia towards a more predominantly anti-inflammatory (M2) phenotype. GMF-KO mice showed significant improvement in motor ability, memory, and cognition. Overall, our results demonstrate that GMF deficiency regulates microglial polarization, which ameliorates neuronal injury and behavioral impairments following TBI in mice and concludes that GMF is a regulator of neuroinflammation and an ideal therapeutic target for the treatment of TBI.
Heliyon
High-fat diet (HFD) is associated with gut microbiome dysfunction and mental disorders. However, the timedependence as to when this occurs is unclear. We hypothesized that a short-term HFD causes colonic tissue integrity changes resulting in behavioral changes. Rats were fed HFD or low-fat diet (LFD) for a month and gut microbiome, colon, and behavior were evaluated. Behavioral despair was found in the HFD group. Although obesity was absent, the HFD group showed increased percent weight gain, epididymal fat tissue, and leptin expression. Moreover, the HFD group had increased colonic damage, decreased expression of the tight junction proteins, and higher lipopolysaccharides (LPS) in serum. Metagenomic analysis revealed that the HFD group had more Bacteroides and less S24-7 which correlated with the decreased claudin-5. Finally, HFD group showed an increase of microglia percent area, increased astrocytic projections, and decreased phospho-mTOR. In conclusion, HFD consumption in a short period is still sufficient to disrupt gut integrity resulting in LPS infiltration, alterations in the brain, and behavioral despair even in the absence of obesity.
Advances in Deoxynivalenol Toxicity Mechanisms: The Brain as a Target
Toxins, 2012
Deoxynivalenol (DON), mainly produced by Fusarium fungi, and also commonly called vomitoxin, is a trichothecene mycotoxin. It is one of the most abundant trichothecenes which contaminate cereals consumed by farm animals and humans. The extent of cereal contamination is strongly associated with rainfall and moisture at the time of flowering and with grain storage conditions. DON consumption may result in intoxication, the severity of which is dose-dependent and may lead to different symptoms including anorexia, vomiting, reduced weight gain, neuroendocrine changes, immunological effects, diarrhea, leukocytosis, hemorrhage or circulatory shock. During the last two decades, many studies have described DON toxicity using diverse animal species as a model. While the action of the toxin on peripheral organs and tissues is well documented, data illustrating its effect on the brain are significantly less abundant. Yet, DON is known to affect the central nervous system. Recent studies have provided new evidence and detail regarding the action of the toxin on the brain. The purpose of the present review is to summarize critical studies illustrating this central action of the toxin and to suggest research perspectives in this field.
Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain
Brain Sciences, 2016
Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.
Effect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage
International Journal of Molecular Sciences
Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood–brain barrier’s (BBB´s) and blood–cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate fu...
Toll-Like Receptor 4 Is Essential in the Development of Abdominal Aortic Aneurysm
PloS one, 2016
Toll-like receptor (TLR) family plays a key role in innate immunity and various inflammatory responses. TLR4, one of the well-characterized pattern-recognition receptors, can be activated by endogenous damage-associated molecular pattern molecules such as high mobility group box 1 (HMGB1) to sustain sterile inflammation. Evidence suggested that blockade of TLR4 signaling may confer protection against abdominal aortic aneurysm (AAA). Herein we aimed to obtain further insight into the mechanism by which TLR4 might promote aneurysm formation. Characterization of the CaCl2-induced AAA model in mice revealed that upregulation of TLR4 expression, localized predominantly to vascular smooth muscle cells (VSMCs), was followed by a late decline during a 28-day period of AAA development. In vitro, TLR4 expression was increased in VSMCs treated with HMGB1. Knockdown of TLR4 by siRNA attenuated HMGB1-enhanced production of proinflammatory cytokines, specifically interleukin-6 and monocyte chemoa...
Magnetic resonance imaging of ischemia viability thresholds and the neurovascular unit
Sensors (Basel, Switzerland), 2013
Neuroimaging has improved our understanding of the evolution of stroke at discreet time points helping to identify irreversibly damaged and potentially reversible ischemic brain. Neuroimaging has also contributed considerably to the basic premise of acute stroke therapy which is to salvage some portion of the ischemic region from evolving into infarction, and by doing so, maintaining brain function and improving outcome. The term neurovascular unit (NVU) broadens the concept of the ischemic penumbra by linking the microcirculation with neuronal-glial interactions during ischemia reperfusion. Strategies that attempt to preserve the individual components (endothelium, glia and neurons) of the NVU are unlikely to be helpful if blood flow is not fully restored to the microcirculation. Magnetic resonance imaging (MRI) is the foremost imaging technology able to bridge both basic science and the clinic via non-invasive real time high-resolution anatomical delineation of disease manifestati...
Role of Innate Immune Receptor TLR4 and its endogenous ligands in epileptogenesis
Pharmacological Research, 2020
Understanding the interplay between the innate immune system, neuroinflammation, and epilepsy might offer a novel perspective in the quest of exploring new treatment strategies. Due to the complex pathology underlying epileptogenesis, no disease-modifying treatment is currently available that might prevent epilepsy after a plausible epileptogenic insult despite the advances in pre-clinical and clinical research. Neuroinflammation underlies the etiopathogenesis of epilepsy and convulsive disorders with Toll-like receptor (TLR) signal transduction being highly involved. Among TLR family members, TLR4 is an innate immune system receptor and lipopolysaccharide (LPS) sensor that has been reported to contribute to epileptogenesis by regulating neuronal excitability. Herein, we discuss available evidence on the role of TLR4 and its endogenous ligands, the high mobility group box 1 (HMGB1) protein, the heat shock proteins (HSPs) and the myeloid related protein 8 (MRP8), in epileptogenesis and post-traumatic epilepsy (PTE). Moreover, we provide an account of the promising findings of TLR4 modulation/inhibition in experimental animal models with therapeutic impact on seizures.
Laboratory Investigation, 2011
In the current study, we explored the role of TNF cluster cytokines on the lipopolysaccharide (LPS)-mediated, synergistic increase in brain injury after hypoxic ischemic insult in postnatal day 7 mice. Pretreatment with moderate doses of LPS (0.3 mg/g) resulted in particularly pronounced synergistic injury within 12 h. Systemic application of LPS alone resulted in a strong upregulation of inflammation-associated cytokines TNFa, LTb, interleukin (IL) 1b, IL6, chemokines, such as CXCL1, and adhesion molecules E-Selectin, P-Selectin and intercellular adhesion molecule-1 (ICAM1), as well as a trend toward increased LTa levels in day 7 mouse forebrain. In addition, it was also associated with strong activation of brain blood vessel endothelia and local microglial cells. Here, deletion of the entire TNF gene cluster, removing TNFa, LTb and LTa completely abolished endotoxin-mediated increase in the volume of cerebral infarct. Interestingly, the same deletion also prevented endothelial and microglial activation following application of LPS alone, suggesting the involvement of these cell types in bringing about the LPS-mediated sensitization to neonatal brain injury.
International Journal of Molecular Sciences, 2022
Systemic inflammation has been implicated in the progression of Alzheimer's disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how ADassociated amyloid beta (Aβ) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16-18-month-old female Tg2576 (Tg) mice, which overproduce human Aβ and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aβ, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1β, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aβ pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aβ. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aβ pathology could contribute to poor outcomes following a systemic inflammatory insult.
Journal of Neuroinflammation, 2011
Background Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses. Methods ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg/kg) and effects on core-body temperature and systemic and CNS cytokine production...
Antimicrobial Peptides and Complement in Neonatal Hypoxia-Ischemia Induced Brain Damage
Frontiers in Immunology, 2015
Hypoxic-ischemic encephalopathy (HIE) is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1-5/1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy, and cognitive disabilities. Even though the brain is considered as an immuneprivileged site, it has innate and adaptive immune response and can produce complement (C) components and antimicrobial peptides (AMPs). Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain. Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS), including neonatal hypoxia-ischemia (HI), resident microglia, and astroglia are the main cells providing immune defense to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI injury and the effect of that balance on the subsequent brain damage.