Resolution Of Neuroinflammation Research Articles

Neuroinflammation and Acetylcholinesterase Inhibitory Potentials of a Spiroketal-Enol Ether Polyyne Isolated from Artemisia pallens Wall. ex DC.

Artemisia pallens Wall. ex DC (Asteraceae) is cultivated for the production of high-value essential oil from its aerial biomass. In this study, the chemical composition of the root (crop-residue) essential oil was investigated for the first time, using column-chromatography, GC-FID, GC-MS, LC-QTOF, and NMR techniques, which led to the identification of twenty constituents, with isolation of (E)-2-(2',4'-hexadiynylidene)-1,6-dioxaspiro [4.5]dec-3-ene (D6). The D6 was evaluated in vitro for neuroinflammation and acetylcholinesterase inhibitory potential. It showed inhibition of neuroinflammation in a concentration-dependent manner with significant inhibition of pro-inflammatory cytokines (TNF-α and IL-6) in LPS-stimulated BV2 microglial cells. D6 did not have any significant effect on the viability of the cells at the therapeutic concentrations. D6 also has shown acetylcholinesterase inhibitory potential (51.90±1.19 %) at the concentration of log 106 nM. The results showed that D6 has a potential role in the resolution of neuroinflammation, and its acetylcholinesterase inhibitory potential directs further investigation of its role in the management of Alzheimer's disease-related pathogenesis.

Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis

Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.

Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation.

Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells. Here, we examined the fate of microglia, BAMs, and recruited macrophages upon neuroinflammation and through resolution. Upon infection, Trypanosoma brucei parasites invaded the brain via its border regions, triggering brain barrier disruption and monocyte infiltration. Fate mapping combined with single-cell sequencing revealed microglia accumulation around the ventricles and expansion of epiplexus cells. Depletion experiments using genetic targeting revealed that resident macrophages promoted initial parasite defense and subsequently facilitated monocyte infiltration across brain barriers. These recruited monocyte-derived macrophages outnumbered resident macrophages and exhibited more transcriptional plasticity, adopting antimicrobial gene expression profiles. Recruited macrophages were rapidly removed upon disease resolution, leaving no engrafted monocyte-derived cells in the parenchyma, while resident macrophages progressively reverted toward a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Thus, brain-resident and recruited macrophages exhibit diverging responses and dynamics during infection and resolution.

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Emerging role of neuregulin-1beta1 in pathogenesis and progression of multiple sclerosis

Acid-Responsive Dual-Targeted Nanoparticles Encapsulated Aspirin Rescue the Immune Activation and Phenotype in Autism Spectrum Disorder.

The treatment of autism spectrum disorder (ASD) is one of the most difficult challenges in neurodevelopmental diseases, because of the unclear pathogenesis research and low brain‐lesion targeting efficiency. Besides, maternal immune activation has been reported as the most mature and widely used model of ASD and aspirin‐triggered lipoxin A4 is a potent anti‐inflammatory mediator being involved in the resolution of neuroinflammation in ASD. Therefore, an aspirin encapsulated cascade drug delivery system (Asp@TMNPs) is established, which can successively target the blood–brain barrier (BBB) and microglial cells and response to the acid microenvironment in lysosome. As a result, the mitochondrial oxidative stress, DNA damage, and inflammation of microglial cells are prominently alleviated. After the treatment of Asp@TMNPs, the social interaction, stereotype behavior, and anxious condition of ASD mice are notably improved and the activation of microglial cells is inhibited. Overall, this system successively penetrates the BBB and targets microglial cells, therefore, it significantly enhances the intracephalic drug accumulation and improves anti‐neuroinflammatory efficacy of aspirin, providing a promising strategy for ASD treatment.

Imeglimin Is Neuroprotective Against Ischemic Brain Injury in Rats-a Study Evaluating Neuroinflammation and Mitochondrial Functions.

Imeglimin is a novel oral antidiabetic drug modulating mitochondrial functions. However, neuroprotective effects of this drug have not been investigated. The aim of this study was to investigate effects of imeglimin against ischemia-induced brain damage and neurological deficits and whether it acted via inhibition of mitochondrial permeability transition pore (mPTP) and suppression of microglial activation. Ischemia in rats was induced by permanent middle cerebral artery occlusion (pMCAO) for 48 h. Imeglimin (135 μg/kg/day) was injected intraperitoneally immediately after pMCAO and repeated after 24 h. Immunohistochemical staining was used to evaluate total numbers of neurons, astrocytes, and microglia as well as interleukin-10 (IL-10) producing cells in brain slices. Respiration of isolated brain mitochondria was assessed using high-resolution respirometry. Assessment of ionomycin-induced mPTP opening in intact cultured primary rat neuronal, astrocytic, and microglial cells was performed using fluorescence microscopy. Treatment with imeglimin significantly decreased infarct size, brain edema, and neurological deficits after pMCAO. Moreover, imeglimin protected against pMCAO-induced neuronal loss as well as microglial proliferation and activation, and increased the number of astrocytes and the number of cells producing anti-inflammatory cytokine IL-10 in the ischemic hemisphere. Imeglimin in vitro acutely prevented mPTP opening in cultured neurons and astrocytes but not in microglial cells; however, treatment with imeglimin did not prevent ischemia-induced mitochondrial respiratory dysfunction after pMCAO. This study demonstrates that post-stroke treatment with imeglimin exerts neuroprotective effects by reducing infarct size and neuronal loss possibly via the resolution of neuroinflammation and partly via inhibition of mPTP opening in neurons and astrocytes.

The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation.

Microglia, the resident immune cells of the brain, can take on a range of pro- or anti-inflammatory phenotypes to maintain homeostasis. However, the sustained activation of pro-inflammatory microglia can lead to a state of chronic neuroinflammation characterized by high concentrations of neurotoxic soluble factors throughout the brain. In healthy brains, the inflammatory processes cease and microglia transition to an anti-inflammatory phenotype, but failure to halt the pro-inflammatory processes is a characteristic of many neurological disorders. The endocannabinoid system has been identified as a promising therapeutic target for chronic neuroinflammation as there is evidence that synthetic and endogenously produced cannabinoids temper the pro-inflammatory response of microglia and may encourage a switch to an anti-inflammatory phenotype. Activation of cannabinoid type 2 (CB2) receptors has been proposed as the mechanism of action responsible for these effects. The abundance of components of the endocannabinoid system in microglia also change dynamically in response to several brain pathologies. This can impact the ability of microglia to synthesize and degrade endocannabinoids or react to endogenous and exogenous cannabinoids. Cannabinoid receptors also participate in the formation of receptor heteromers which influences their function specifically in cells that express both receptors, such as microglia. This creates opportunities for drug-drug interactions between CB2 receptor-targeted therapies and other classes of drugs. In this article, we review the roles of pro- and anti-inflammatory microglia in the development and resolution of neuroinflammation. We also discuss the fluctuations observed in the components of the endocannabinoid in microglia and examine the potential of CB2 receptors as a therapeutic target in this context.

Delayed microglial activation associated with the resolution of neuroinflammation in a mouse model of sublethal endotoxemia-induced systemic inflammation

Systemic inflammation affects brain functions. In our previous study in which lipopolysaccharide (LPS) was injected intraperitoneally into mice at sublethal doses, choroid plexus macrophages produced interleukin-1β and stimulated neighboring stromal cells. Activated stromal cells stimulate choroid plexus epithelial cells, and then choroid plexus epithelium-derived cytokines enter the brain parenchyma and stimulate astrocytes. Stimulated astrocytes then produce cytokines such as CCL11, CXCL10 and G-CSF and change the brain parenchymal microenvironment. However, the effects of an altered brain microenvironment on other brain cells remain to be determined. In the present study, we hypothesized that microglia are activated in response to astrocyte-induced changes in the brain microenvironment. Using the brains of mice treated with intraperitoneal LPS injection, Luminex multiplex cytokine immunoassays revealed increased hippocampal concentrations of CCL11, CXCL10 and G-CSF at 48 h after systemic LPS challenge. The concentrations of all cytokines examined returned to control levels at 72 h after LPS injection, which indicated a resolution of the neuroinflammation. Immunohistochemistry revealed that microglia were hypertrophied in mice at 48 h after systemic LPS challenge. Following isolation of microglial cells from the brain using magnetic-activated cell sorting, gene expression assays were performed with real-time reverse transcriptase-polymerase chain reaction. Isolated microglial cells exhibited much higher gene expression of the receptors for CCL11, CXCL10 and G-CSF than other brain cells. Microglial cells isolated from the brains of mice at 48 h after systemic LPS challenge exhibited the M2-like phenotype. In conclusion, microglial hypertrophy occurs following astrocytic reactions in a mouse model of sublethal endotoxemia-induced systemic inflammation, and hypertrophic microglia are polarized toward the M2-like phenotype and involved in the resolution of neuroinflammation.

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation.

Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.

Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis

Sepsis-associated encephalopathy (SAE) increases not only morbidity and mortality but has been associated with long-lasting mental impairment after hospital discharge in septic patients. Recently, studies have shown that these mental impairments are caused by infection-induced neuroinflammation. However, the role of T cells in the pathogenesis of SAE and mental impairments remains unclear. Thus, in this study, we aimed to clarify how immune cells, especially T cells, influence the development and recovery of these disorders. In the cecal slurry (CS)-induced septic mouse model, we performed three different kinds of behavioral tests, open-field test, marble burying test, and forced swimming test, and observed anxiety-like behavior in septic mice. Additionally, increased interleukin (IL)-1β and IL-6 expression levels, and infiltration of neutrophils and T cells were examined in the brain of septic mice, 10 days after sepsis onset. Twenty days after sepsis onset, the septic mice could recover the number of astrocytes. At day 30, expression levels of IL-1β and tumor necrosis factor (TNF)-α returned to normal levels in the cerebral cortex of septic mice. Interestingly, resolution of neuroinflammation and alleviation of depression were delayed in septic mice treated with FTY720, which inhibits sphingosine-1-phosphate (S1P)-dependent lymphocyte egress from lymph nodes. On analyzing the brain T cells with or without FTY720 in septic mice, the FTY720 untreated mice presented increased regulatory T cells (Treg) and Th2 cells in the brain, whereas the FTY720 treated mice demonstrated increased Th17 in the brain at day 30. Furthermore, in FTY720 treated septic mice, the number of astrocytes in the cerebral cortex remained reduced at day 30. These results suggest that infiltrated Treg and Th2 cells contribute to the attenuation SAE and alleviate SAE-induce mental disorder by resolving neuroinflammation in the chronic phase of sepsis.

Communications Between Peripheral and the Brain-Resident Immune System in Neuronal Regeneration After Stroke.

Cerebral ischemia may cause irreversible neural network damage and result in functional deficits. Targeting neuronal repair after stroke potentiates the formation of new connections, which can be translated into a better functional outcome. Innate and adaptive immune responses in the brain and the periphery triggered by ischemic damage participate in regulating neural repair after a stroke. Immune cells in the blood circulation and gut lymphatic tissues that have been shaped by immune components including gut microbiota and metabolites can infiltrate the ischemic brain and, once there, influence neuronal regeneration either directly or by modulating the properties of brain-resident immune cells. Immune-related signalings and metabolites from the gut microbiota can also directly alter the phenotypes of resident immune cells to promote neuronal regeneration. In this review, we discuss several potential mechanisms through which peripheral and brain-resident immune components can cooperate to promote first the resolution of neuroinflammation and subsequently to improved neural regeneration and a better functional recovery. We propose that new insights into discovery of regulators targeting pro-regenerative process in this complex neuro-immune network may lead to novel strategies for neuronal regeneration.

A selective p38\u03b1/\u03b2 MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

BackgroundChronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models.MethodsIn this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPK inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay.ResultsNJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies.ConclusionTaken together, a selective p38α/β MAPK inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPK inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs.

An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events

The inflammation process represents of a dynamic series of phenomena that manifest themselves with an intense vascular reaction. Neuroinflammation is a reply from the central nervous system (CNS) and the peripheral nervous system (PNS) to a changed homeostasis. There are two cell systems that mediate this process: the glia of the CNS and the lymphocites, monocytes, and macrophages of the hematopoietic system. In both the peripheral and central nervous systems, neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, and in neuropsychiatric illnesses, such as depression and autism spectrum disorders. The resolution of neuroinflammation is a process that allows for inflamed tissues to return to homeostasis. In this process the important players are represented by lipid mediators. Among the naturally occurring lipid signaling molecules, a prominent role is played by the N-acylethanolamines, namely N-arachidonoylethanolamine and its congener N-palmitoylethanolamine, which is also named palmitoylethanolamide or PEA. PEA possesses a powerful neuroprotective and anti-inflammatory power but has no antioxidant effects per se. For this reason, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treating neuroinflammation. The aim of this review is to discuss the role of ultramicronized PEA and co-ultramicronized PEA with luteolin in several neurological diseases using preclinical and clinical approaches.

The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

BackgroundNeuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer’s disease (AD). N-6 polyunsaturated fatty acids (PUFA) and molecules derived from them, including linoleic acid- and arachidonic acid-derived lipid mediators, are known to have pro-inflammatory properties in the periphery; however, this has yet to be tested in the brain. Lowering the consumption of n-6 PUFA is associated with a decreased risk of depression and AD in human observational studies. The purpose of this study was to investigate the inflammation-modulating effects of lowering dietary n-6 PUFA in the mouse hippocampus.MethodsC57BL/6 male mice were fed either an n-6 PUFA deprived (2% of total fatty acids) or an n-6 PUFA adequate (23% of total fatty acids) diet from weaning to 12 weeks of age. Animals then underwent intracerebroventricular surgery, in which lipopolysaccharide (LPS) was injected into the left lateral ventricle of the brain. Hippocampi were collected at baseline and following LPS administration (1, 3, 7, and 14 days). A microarray (n = 3 per group) was used to identify candidate genes and results were validated by real-time PCR in a separate cohort of animals (n = 5–8 per group).ResultsMice administered with LPS had significantly increased Gene Ontology categories associated with inflammation and immune responses. These effects were independent of changes in gene expression in any diet group. Results were validated for the effect of LPS treatment on astrocyte, cytokine, and chemokine markers, as well as some results of the diets on Ifrd2 and Mfsd2a expression.ConclusionsLPS administration increases pro-inflammatory and lipid-metabolizing gene expression in the mouse hippocampus. An n-6 PUFA deprived diet modulated inflammatory gene expression by both increasing and decreasing inflammatory gene expression, without impairing the resolution of neuroinflammation following LPS administration.

Resolution of neuroinflammation: mechanisms and potential therapeutic option

The central nervous system (CNS) is comprised by an elaborate neural network that is under constant surveillance by tissue-intrinsic factors for maintenance of its homeostasis. Invading pathogens or sterile injuries might compromise vitally the CNS integrity and function. A prompt anti-inflammatory response is therefore essential to contain and repair the local tissue damage. Although the origin of the insults might be different, the principles of tissue backlashes, however, share striking similarities. CNS-resident cells, such as microglia and astrocytes, together with peripheral immune cells orchestrate an array of events that aim to functional restoration. If the acute inflammatory event remains unresolved, it becomes toxic leading to progressive CNS degeneration. Therefore, the cellular, molecular, and biochemical processes that regulate inflammation need to be on a fine balance with the intrinsic CNS repair mechanisms that influence tissue healing. The purpose of this review is to highlight aspects that facilitate the resolution of CNS inflammation, promote tissue repair, and functional recovery after acute injury and infection that could potentially contribute as therapeutic interventions.

N-3 Polyunsaturated Fatty Acids and the Resolution of Neuroinflammation.

In the past few decades, as a result of their anti-inflammatory properties, n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), have gained greater importance in the regulation of inflammation, especially in the central nervous system (in this case known as neuroinflammation). If sustained, neuroinflammation is a common denominator of neurological disorders, including Alzheimer’s disease and major depression, and of aging. Hence, limiting neuroinflammation is a real strategy for neuroinflammatory disease therapy and treatment. Recent data show that n-3 LC-PUFAs exert anti-inflammatory properties in part through the synthesis of specialized pro-resolving mediators (SPMs) such as resolvins, maresins and protectins. These SPMs are crucially involved in the resolution of inflammation. They could be good candidates to resolve brain inflammation and to contribute to neuroprotective functions and could lead to novel therapeutics for brain inflammatory diseases. This review presents an overview 1) of brain n-3 LC-PUFAs as precursors of SPMs with an emphasis on the effect of n-3 PUFAs on neuroinflammation, 2) of the formation and action of SPMs in the brain and their biological roles, and the possible regulation of their synthesis by environmental factors such as inflammation and nutrition and, in particular, PUFA consumption.

CD4+ T cells regulate Mouse Hepatitis Virus induced activation of microglia

Abstract Multiple Sclerosis (MS) is a human neurological disease characterised by neuroinflammatory demyelination and axonal loss. Studies in MS are focussed to understand the process of demyelination driven by B/T lymphocytes, but we have limited knowledge about direct virus-induced neural cell dystrophy and the role of innate immunity in MS. Our studies employ Mouse Hepatitis Virus (MHV) induced neuroinflammatory model to understand microglia-mediated myelin stripping as a mechanism of demyelination. Microglia are the CNS resident macrophages that lie at the intersection of immune response and neurodegenerative process. They control the initiation, progression and resolution of neuroinflammation in the CNS. One of our studies in MHV model demonstrated that in the absence of CD4+ T cells, mice are more susceptible to acute encephalitis and chronic demyelination. In order to understand the mechanism of anti-viral immune response, we have investigated the role of microglia upon CD4+ T cell modulation. Results from our studies showed that a higher number of Iba1+ microglial cells persist in the brain parenchyma of CD4−/− mice at the chronic infection stage in comparison to the WT mice. Real-time qPCR screening of inflammatory markers like IL6, IL10, IL12, CXCL10, CCL5, CD86 and CD163 presented a consistent proinflammatory microenvironment in the CNS and comparative lower expression of Btk1 and Arg1 in the brains of CD4−/− mice. In conclusion, our findings propose that further in vitro and in vivo studies are necessary to understand the role of CD4+ T cell activation and maturation which might help in favouring a shift towards adaptive immunity, differential microglial activation, viral clearance and maintaining neural homeostasis.

Atractylenolide III ameliorates cerebral ischemic injury and neuroinflammation associated with inhibiting JAK2/STAT3/Drp1-dependent mitochondrial fission in microglia

BackgroundInflammation is a major contributor to stroke pathology, making it a promising strategy for intervention. Microglia, the resident macrophages in the brain, play essential roles in both the generation and resolution of neuroinflammation. In particular, mitochondrial homeostasis is critical for microglial function and its dysregulation is involved in the pathogenesis of ischemic stroke. Atractylenolide III (A III), a sesquiterpene lactone found in Atractylodes macrocephala Koidz, has been shown to have an inhibitory effect on inflammation. However, its effect specifically on neuroinflammation and microglial mitochondrial homeostasis following stroke remains elusive. HypothesisWe hypothesized that A III protects against brain ischemia through inhibition of neuroinflammation mediated by JAK2/STAT3/Drp1-dependent mitochondrial fission. MethodsThe neuroprotective and anti-neuroinflammatory effects of A III were investigated in vivo in mice with transient occlusion to the middle cerebral artery (MCAO) and in vitro in oxygen glucose deprivation-reoxygenation (OGDR)-stimulated primary microglia from mice. ResultsA III and AG490, an inhibitor of JAK2, treatment reduced brain infarct size, restored cerebral blood flow (CBF), ameliorated brain edema and improved neurological deficits in MCAO mice. Furthermore, A III and AG490 inhibited mRNA and protein expressions of proinflammatory (IL-1β, TNF-α, and IL-6) and anti-inflammatory cytokines in both MCAO mice and OGDR-stimulated primary microglia. The JAK2/STAT3 pathway was effectively suppressed by A III, similar to the effect of AG490 treatment. In addition, A III and AG490 treatments significantly decreased Drp1 phosphorylation, translocation and mitochondrial fission in primary microglia stimulated with OGDR for 24 h. ConclusionOur study demonstrated that A III was able to reduce complications associated with ischemia through inhibiting neuroinflammation, which was mediated in part by JAK2/STAT3-dependent mitochondrial fission in microglia.

Increased brain docosahexaenoic acid has no effect on the resolution of neuroinflammation following intracerebroventricular lipopolysaccharide injection

Resolution of inflammation in the periphery was once thought to be a passive process, but new research now suggests it is an active process mediated by specialized pro-resolving lipid mediators (SPM) derived from omega-3 polyunsaturated fatty acids (n-3 PUFA). However, this has yet to be illustrated in neuroinflammation. The purpose of this study was to measure resolution of neuroinflammation and to test whether increasing brain docosahexaenoic acid (DHA) affects the resolution of neuroinflammation.C57Bl/6 mice, fat-1 mice and their wildtype littermates, fed either fish oil or safflower oil, received lipopolysaccharide (LPS) in the left lateral ventricle. Animals were then euthanized at various time points for immunohistochemistry, gene expression, and lipidomic analyses.Peak microglial activation was observed at 5 days post-surgery and the resolution index was 10 days. Of the approximately 350 genes significantly changed over the 28 days post LPS injection, 130 were uniquely changed at 3 days post injection. No changes were observed in the bioactive mediator pools. However, a few lysophospholipid species were decreased at 24hr post surgery. When brain DHA is increased, microglial cell density did not resolve faster and did not alter gene expression.In conclusion, resolution of neuroinflammation appears to be independent of SPM. Increasing brain DHA had no effect in this model.

TGF-β2 and TGF-β3 from cultured β-amyloid-treated or 3xTg-AD-derived astrocytes may mediate astrocyte-neuron communication.

Astrocytes participate in the development and resolution of neuroinflammation in numerous ways, including the release of cytokines and growth factors. Among many, astrocytes release transforming growth factors beta (TGF-β) TGF-β1, TGF-β2 and TGF-β3. TGF-β1 is the most studied isoform, while production and release of TGF-β2 and TGF-β3 by astrocytes have been poorly characterized. Here, we report that purified cultures of hippocampal astrocytes produce mainly TGF-β3 followed by TGF-β2 and TGF-β1. Furthermore, astrocytes release principally the active form of TGF-β3 over the other two. Changes in release of TGF-β were sensitive to the calcineurin (CaN) inhibitor FK506. Starvation had no effect on TGF-β1 and TGF-β3 while TGF-β2 mRNA was significantly up-regulated in a CaN-dependent manner. We further investigated production and release of astroglial TGF-β in Alzheimer's disease-related conditions. Oligomeric β-amyloid (Aβ) down-regulated TGF-β1, while up-regulating TGF-β2 and TGF-β3, in a CaN-dependent manner. In cultured hippocampal astrocytes from 3xTg-AD mice, TGF-β2 and TGF-β3, but not TGF-β1, were up-regulated, and this was CaN-independent. In hippocampal tissues from symptomatic 3xTg-AD mice, TGF-β2 was up-regulated with respect to control mice. Finally, treatment with recombinant TGF-βs showed that TGF-β2 and TGF-β3 significantly reduced PSD95 protein in cultured hippocampal neurons, and this effect was paralleled by conditioned media from Aβ-treated astrocytes or from astrocytes from 3xTg-AD mice. Taken together, our data suggest that TGF-β2 and TGF-β3 are produced by astrocytes in a CaN-dependent manner and should be investigated further in the context of astrocyte-mediated neurodegeneration.