Systemic Neuroinflammation Research Articles

The involvement of proinflammatory cytokines in the pathogenesis of audiogenic epilepsy

Epilepsy is a heterogeneous disease, which determines the relevance of investigating the mechanisms of pathogenesis of its various types, including reflex epilepsy. Pharmacotherapy is common for the treatment of patients with epilepsy, however, despite the significant recent achievements, 20-30% of patients remain resistant to the ongoing treatment. The urgency of creating new antiepileptic drugs, in particular, immune ones is due not only to a significant proportion of pharmacoresistant cases, but also to the struggle for the quality of life of patients. The neuroinflammation system in animals with different genetically determined audiogenic epilepsy proneness was investigated. These genetic groups were Krushinsky–Molodkina rats (tonic seizures of maximum intensity in response to the action of sound) and “0” strain (control group, non-convulsive phenotype). The main proinflammatory cytokines levels in the dorsal striatum and brain stem in rats of these genetic groups were measured by multiplex immunofluorescence assay. Background levels of IL-1â, IL-6 and TNFá in the dorsal striatum of KM rats were significantly lower than in the control “0” strain rats, whereas in the brain stem in the “background” levels of these metabolites did not differ. Four hours after the sound exposure, the TNFá level in the dorsal striatum of KM rats was significantly lower than in “0” rats. In KM rats, after the sound exposure and subsequent tonic seizures, the levels of IL-1â and IL-6 in the dorsal striatum were significantly higher than in the background. The IL-2 content was not detected in the background in KM rats, whereas after audiogenic seizures its level was 14.01 pg/ml. In the brain stem of KM rats, the levels of IL-1â and TNFá after audiogenic seizures were significantly lower than in the background. In rats of the “0” strain, cytokine levels in the dorsal striatum after the sound exposure did not differ from those in the background, while IL-1ß levels in their brain stem were significantly lower than the background state. Particular modulating role of the studied proinflammatory cytokines in the pathogenesis of audiogenic epilepsy is assumed, as well as certain possibility of anti-inflammatory and immune drugs application in anticonvulsant and antiepileptic therapy.

Glymphatic system: a gateway for neuroinflammation.

The glymphatic system is a relatively recently identified fluid exchange and transport system in the brain. Accumulating evidence indicates that glymphatic function is impaired not only in central nervous system disorders but also in systemic diseases. Systemic diseases can trigger the inflammatory responses in the central nervous system, occasionally leading to sustained inflammation and functional disturbance of the central nervous system. This review summarizes the current knowledge on the association between glymphatic dysfunction and central nervous system inflammation. In addition, we discuss the hypothesis that disease conditions initially associated with peripheral inflammation overwhelm the performance of the glymphatic system, thereby triggering central nervous system dysfunction, chronic neuroinflammation, and neurodegeneration. Future research investigating the role of the glymphatic system in neuroinflammation may offer innovative therapeutic approaches for central nervous system disorders.

Electroacupuncture attenuates inflammatory pain via peripheral cannabinoid receptor type 1 signaling pathway in mice

Pain is strongly associated with neuro-immune activation. Thus, the emerging role of the endocannabinoid system in neuro-inflammation is important. Acupuncture has been used for over 2500 years and is widely accepted for the management of pain. Our study aimed to investigate the effects of electroacupuncture on the regulation of cannabinoid receptor type 1 within the peripheral nervous system. Inflammatory pain was induced by injecting Complete Freund’s adjuvant to induce mechanical and thermal hyperalgesia. Electroacupuncture significantly attenuated the mechanical and thermal sensitivities, and AM251, a cannabinoid receptor type 1 antagonist, eliminated these effects. Dual immunofluorescence staining demonstrated that electroacupuncture elevated expression of cannabinoid receptor type 1, co-localized with Nav 1.8. Furthermore, electroacupuncture significantly reduced levels of Nav 1.8 and COX-2 by western blot analysis, but not vice versa as AM251 treatment. Our data indicate that electroacupuncture mediates antinociceptive effects through peripheral endocannabinoid system signaling pathway and provide evidence that electroacupuncture is beneficial for pain treatment.

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.

Neurometabolic alterations in the nucleus accumbens of smokers assessed with 1 H magnetic resonance spectroscopy: The role of glutamate and neuroinflammation.

Tobacco use is one of the leading causes of premature death and morbidity worldwide. For smokers trying to quit, relapse rates are high, even after prolonged periods of abstinence. Recent findings in animal models highlight the role of alterations in glutamatergic projections from the prefrontal cortex onto the nucleus accumbens (NAc) in relapse vulnerability. Moreover, inflammatory responses in the NAc have been reported during withdrawal. A novel proton magnetic resonance spectroscopy (1 H-MRS) protocol was applied in humans to measure molar concentrations for glutamate, its sum with glutamine (Glx), and myoinositol plus glycine (mI+Gly) in the NAc (19 smokers, 20 matched controls). Smokers were measured at baseline and during withdrawal and satiation. No difference between groups or smoking states was found for glutamate or Glx, but, in smokers, stronger craving and more severe nicotine dependence were associated with lower baseline glutamate and Glx levels, respectively. Interestingly, mI+Gly concentrations were higher during withdrawal than baseline and correlated negatively with nicotine dependence severity and pack years of smoking. The lack of glutamatergic changes between groups and smoking states may imply that glutamate homeostasis is not significantly altered in smokers or that changes are too small for detection by 1 H-MRS. Moreover, the observed increase in mI+Gly may imply that neuroinflammatory processes occur in the NAc during nicotine withdrawal. These findings shed light on neurobiological relapse mechanisms in smokers and may provide the opportunity to develop more effective treatment options targeting the glutamate and neuroinflammation system.

Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.

ObjectiveComplement activation is instrumental in the pathogenesis of Hypoxic-ischemic encephalopathy (HIE), a significant cause of neonatal mortality and disability worldwide. Therapeutic hypothermia (HT), the only available treatment for HIE, only modestly improves outcomes. Complement modulation as a therapeutic adjunct to HT has been considered, but is challenging due to the wide-ranging role of the complement system in neuroinflammation, homeostasis and neurogenesis in the developing brain. We sought to identify potential therapeutic targets by measuring the impact of treatment with HT on complement effector expression in neurons and glia in neonatal HIE, with particular emphasis on the interactions between microglia and C1q.MethodsThe Vannucci model was used to induce HIE in term-equivalent rat pups. At P10-12, pups were randomly assigned to three different treatment groups: Sham (control), normothermia (NT), and hypothermia (HT) treatment. Local and systemic complement expression and neuronal apoptosis were measured by ELISA, TUNEL and immunofluorescence labeling, and differences compared between groups.ResultsTreatment with HT is associated with decreased systemic and microglial expression of C1q, decreased systemic C5a levels, and decreased microglial and neuronal deposition of C3 and C9. The effect of HT on cytokines was variable with decreased expression of pro and anti-inflammatory effectors. HT treatment was associated with decreased C1q binding on cells undergoing apoptosis.ConclusionOur data demonstrate the extreme complexity of the immune response in neonatal HIE. We propose modulation of downstream effectors C3a and C5a as a therapeutic adjunct to HT to enhance neuroprotection in the developing brain.

FNDC5/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective.

Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND.

Network-based approach to identify molecular signatures in the brains of depressed suicides

BackgroundSuicide is a serious and global health problem that has a strong association with major depressive disorder (MDD). Weighted gene co-expression network analysis (WGCNA) was performed for the construction of a co-expression network to get important gene modules associated with depressed suicide. MethodsTranscriptome sequencing data from dorsolateral prefrontal cortex was used, which included 29 non-psychiatric controls (CON), 21 MDD suicides (MDD-S) and 9 MDD non-suicides (MDD-NS) of medication-free sudden death individuals. ResultsThe highest correlation in the module-traits relationship was discovered between the black module and suicide (r = -0.30, p = 0.024) as well as MDD (r = -0.34, p = 0.010).Furthermore, the expression levels of genes decreased progressively across the three groups (CON>MDD-NS>MDD-S). Therefore, the genes in the black module was selected for subsequent analyses. Protein-Protein Interaction Network found that the top 10 hub genes were somehow involved in depressed suicide including JUN, FOS, ATF3, MYC, EGR1, FOSB, DUSP1, NFKBIA, TLR2, NR4A1. Most of the GO terms were enriched in cell death and apoptosis and KEGG was mainly enriched in MAPK pathway. Cell Type–Specific Analysis found these genes were significantly enriched in endothelial and microglia (p<0.000) cell types. In addition, 92 genes in this module had at least one highly significant differentially methylated positions between MDD-S and controls. ConclusionCell death and apoptosis may participate in the interplay between depressed suicide and neuro-inflammation system.

The Regulatory Role of miRNAs in Ethanol-induced TLR4 Activation and Neuroinflammation

Alcohol is a neurotoxic compound and its abuse can induce brain damage and neurodegeneration. Evidence from the last decade demonstrates the critical role of the innate immune system in neuroinflammation associated with alcohol abuse. In this review, we discuss the role of miRNAs as regulators of immune Toll-like receptors (TLR4), the neuroimmune response associated with alcohol abuse, and the importance of glial extracellular vesicles in amplifying neuroinflammation. Current studies demonstrate the role of glial extracellular vesicles/exosomes in extending neuroinflammation, and the importance of miRNAs as key regulators of different biological functions. However, dysregulation of miRNAs also participates in neurological and neurodegenerative diseases associated with neuroinflammation. Recent findings indicate the possibility of circulating miRNAs being used as biomarkers to screen neurological and neuroinflammatory disorders as early diagnosis and therapy. This article highlights the role of miRNAs in regulating neuroinflammation associated with alcohol abuse and the importance of glial extracellular vesicles/exosomes in extending neuroinflammation.

Endocannabinoid regulation of amyloid-induced neuroinflammation

The modulation of endocannabinoid (EC) levels and the activation of cannabinoid receptors are seen as promising therapeutic strategies in a variety of diseases, including Alzheimer's disease (AD). We aimed to evaluate the effect of the pharmacologic and genetic inhibition of anandamide-degrading enzyme in a mouse model of AD (5xFAD). Pharmacologic inhibition of the fatty acid amide hydrolase (FAAH) had little impact on the expression of key enzymes and cytokines and also on the cognitive impairment, plaque deposition, and gliosis in 5xFAD mice. CB1 blockade exacerbated inflammation in this transgenic mouse model of AD. The genetic inactivation of FAAH led to increases in the expression of inflammatory cytokines. At the same time, FAAH-null 5xFAD mice exhibited a behavioral improvement in spatial memory that was independent of the level of anxiety and was not CB1 mediated. Finally, mice lacking FAAH showed diminished soluble amyloid levels, neuritic plaques, and gliosis. These data reinforce the notion of a role for the EC system in neuroinflammation and open new perspectives on the relevance of modulating EC levels in the inflammed brain.

Editorial: Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury.

The current research topic and eBook “Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury” was initiated as a reaction to the rapidly expanding literature on inflammatory mechanisms in the pathophysiology of acute brain injuries. The scope of this compilation of reviews, opinion, and original research articles was to give a broad overview of the diverse cellular compartments and mechanisms involved in the inflammatory response to brain tissue injury. Although a specific aspect of the pathophysiology of acute brain injuries, the immune system interacts in highly complex as well as diverse mechanisms with the damaged brain. On one side acute brain lesions, such as brain ischemia, hemorrhage or traumatic injury, induce a local neuroinflammatory reaction, wherein microglial cells represent the local immune cells (Benakis et al., 2015; Lourbopoulos et al., 2015). This local inflammatory response has a major impact on outcome with differential effects during the phases of post-stroke lesion evolution and recovery (Shichita et al., 2014). Intriguingly, besides abundant evidence on post-stroke neuroinflammation immunological mechanisms similar mechanisms are also observed in traumatic brain injuries (Schwarzmaier and Plesnila, 2014), intracerebral hemorrhage (Mracsko and Veltkamp, 2014) and even ethanol-induced neurotoxicity (Alfonso-Loeches et al., 2014; Sokolowski et al., 2014) or direct application of exogenous pathogens (Gullo et al., 2014) with functional consequences for neuronal outcome. Moreover, Gauberti et al. (2014) present an overview on state-of-the-art molecular magnetic resonance imaging of neuroinflammatory markers. In recent years also the molecular pathways and effector molecules of inflammation-induced neurotoxicity after acute injuries have been investigated in great detail: Murray et al. (2015) describe in their review the prominent role of the pro-inflammatory cytokine IL-1, Orsini et al. (2014) give an overview on the complement system in neuroinflammation, while Albert-Weissenberger et al. (2014a) focus on the contribution of the kallikrein-kinin system in traumatic brain injury and Zhao et al. (2014) review the current knowledge on programed death-1/programed death ligand signaling. In addition to the activation of local inflammatory pathways in the injured brain, invasion of peripheral immune cells to the brain is a critical step in secondary neuroinflammation. Gelderblom et al. (2014) review the role of gdT cells as a pro-inflammatory invariant T cell subpopulation recruited to the injured brain. In contrast, Urra et al. (2014) discuss potential mechanisms of antigen-specific autoimmunity after acute brain injury. In addition, the original research article by Kim et al. (2014) underlines that the cellular immune response to ischemic brain injury might differ substantially between commonly used mouse strains. In addition to an overview and discussion of basic mechanisms and involved pathways in secondary neuroinflammation after acute brain injury, our research topic also contains several reviews and original articles on novel therapeutic approaches to modulate the immune response. Rissiek et al. (2014) introduce nanobodies as a novel tool for targeting neuroinflammation. Brunkhorst et al. (2014) provide an overview on the promising approach of blocking cellular neuroinflammation with Fingolimod. Bodhankar et al. (2014) review the current literature on targeting the PD-L1 and PD-L2 pathways. The original article by Mouihate (2014) reports a novel role for hormonal replacement therapy in neuroinflammation and the original article by Albert-Weissenberger et al. (2014b) the use of C1-inhibitors in a cortical cryolesion model. Dotson et al. (2014) have tested the use of recombinant TCR ligand with differential effects in young and old mice (see also commentary by Pennypacker, 2014). In summary this research topic gathered contributions from the leading laboratories working in the field of secondary neuroinflammation after brain injury with nearly 100 authors from 4 continents. We are confident that this compilation covers most established and emerging research questions in this specific research field and presents an up-to-date overview on inflammatory mechanisms and drug targets in acute brain injuries.

Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis.

The immune response after brain injury is highly complex and involves both local and systemic events at the cellular and molecular level. It is associated to a dramatic over-activation of enzyme systems, the expression of proinflammatory genes and the activation/recruitment of immune cells. The complement system represents a powerful component of the innate immunity and is highly involved in the inflammatory response. Complement components are synthesized predominantly by the liver and circulate in the bloodstream primed for activation. Moreover, brain cells can produce complement proteins and receptors. After acute brain injury, the rapid and uncontrolled activation of the complement leads to massive release of inflammatory anaphylatoxins, recruitment of cells to the injury site, phagocytosis and induction of blood brain barrier (BBB) damage. Brain endothelial cells are particularly susceptible to complement-mediated effects, since they are exposed to both circulating and locally synthesized complement proteins. Conversely, during neurodegenerative disorders, complement factors play distinct roles depending on the stage and degree of neuropathology. In addition to the deleterious role of the complement, increasing evidence suggest that it may also play a role in normal nervous system development (wiring the brain) and adulthood (either maintaining brain homeostasis or supporting regeneration after brain injury). This article represents a compendium of the current knowledge on the complement role in the brain, prompting a novel view that complement activation can result in either protective or detrimental effects in brain conditions that depend exquisitely on the nature, the timing and the degree of the stimuli that induce its activation. A deeper understanding of the acute, subacute and chronic consequences of complement activation is needed and may lead to new therapeutic strategies, including the ability of targeting selective step in the complement cascade.

Wogonin attenuates endotoxin‐induced prostaglandin E2 and nitric oxide production via Src‐ERK1/2‐NFκB pathway in BV‐2 microglial cells

Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti-inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti-inflammatory function in BV2 microglial cells after LPS/INFγ administration. Wogonin not only inhibited LPS/ INFγ-induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFγ-induced expression of iNOS and COX-2 in the same concentration range. While LPS/INFγ-induced expression of P-p65 and P-IκB was inhibited by wogonin-only weak inhibition on P-p38 and P-JNK were observed, whereas it significantly attenuated the P-ERK1/2 and its upstream activators P-MEK1/2 and P-Src in a parallel concentration-dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFγ-stimulated BV2 cells is attributed mainly to interference in the Src-MEK1/2-ERK1/2-NFκB-signaling pathway.

The chemokine system in neuroinflammation: an update.

Chemokines and their receptors govern physiologic and pathologic leukocyte trafficking. The function of the chemokine system may be of particular interest for hematogenous leukocyte infiltration of the central nervous system (CNS) because of the distinct character of CNS inflammation and the exquisite specificity with which the chemokine system regulates cellular migration events. This review summarizes recent information about the expression and function of elements of the chemokine system in CNS inflammatory processes. Animal models of CNS demyelinating disease and the corresponding human disorder, multiple sclerosis are both considered.