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Proposal mechanism of IFNGR and AMPA receptor GluR1 complex signaling. IFNGR couples with AMPA receptor GluR1 exclusively in neurons. IFN-activates JAK12/ STAT1. Then, activated STAT1 induces cAMP elevation and the following PKA activation. The phosphorylation of GluR1 at Ser-845 position (S845) elicits Ca 2 influx and the subsequent NO production. NO reduces the intracellular ATP level by inhibition of mitochondrial respiratory chain, leading to neuronal dysfunction.
Source publication
Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that plays a pivotal role in pathology of diseases in the central nervous system (CNS), such as multiple sclerosis. However, the direct effect of IFN-gamma on neuronal cells has yet to be elucidated. We show here that IFN-gamma directly induces neuronal dysfunction, which appears as dendrit...
Context in source publication
Context 1
... present study is the first to demonstrate that IFN-directly induces neuronal dys- function through a unique neuron-specific IFNGR and AMPA receptor GluR1 complex and that IFN-phos- phorylates GluR1 by JAK12/STAT1 pathway. Figure 7 shows the proposal mechanism of IFNGR and AMPA receptor signaling. Exclusively in neurons, IFNGR cou- ples with AMPA receptor GluR1. ...
Citations
... Of note, during pathological inflammatory processes, neurotransmitter receptors modulation can also be exerted through the formation of functional complexes with CKs receptors. Interferon-γ (IFN-γ), a proinflammatory cytokine secreted by T cells, is able to induce neuronal dysfunction in cortical neurons enhancing glutamate neurotoxicity through the formation of a neuron-specific, calcium-permeable AMPAR/IFN-γ receptor complex through the binding with AMPAR subunit GluRl [39]. ...
The central nervous system (CNS) is finely protected by the blood–brain barrier (BBB). Immune soluble factors such as cytokines (CKs) are normally produced in the CNS, contributing to physiological immunosurveillance and homeostatic synaptic scaling. CKs are peptide, pleiotropic molecules involved in a broad range of cellular functions, with a pivotal role in resolving the inflammation and promoting tissue healing. However, pro-inflammatory CKs can exert a detrimental effect in pathological conditions, spreading the damage. In the inflamed CNS, CKs recruit immune cells, stimulate the local production of other inflammatory mediators, and promote synaptic dysfunction. Our
understanding of neuroinflammation in humans owes much to the study of multiple sclerosis (MS), the most common autoimmune and demyelinating disease, in which autoreactive T cells migrate from the periphery to the CNS after the encounter with a still unknown antigen. CNS-infiltrating T cells produce pro-inflammatory CKs that aggravate local demyelination and neurodegeneration. This review aims to recapitulate the state of the art about CKs role in the healthy and inflamed CNS, with focus on recent advances bridging the study of adaptive immune system and neurophysiology.
... A low glutamate/GABA ratio of inhibitory/excitatory synaptic transmission also causes increased levels of IFN-γ in the plasma of autistic patients. IFN-γ is a unique, neuronspecific, calcium-permeable receptor complex with AMPA receptor subunit GluR1which induces neurotoxicity via glutamate excitotoxicity in autistic patients [87]. An imbalance in glutamate/GABA ratio leads to impaired plasma levels of TNF-α, IL-6, IFN-γ and IFI16 that cause neuroinflammation contributing to the etiology of autism [88]. ...
The bidirectional communication among the different peptide neurotransmitters and their receptors influences brain, immunity, and behavior. Among the peptide neurotransmitters, Glutamate is the primary excitatory while; gamma-aminobutyrate (γ-GABA), is the inhibitory neurotransmitter. Glutamatergic/GABAergic imbalances are seen in many neurological and autoimmune disorders. With an aim to understand more deeply the intricacies of glutamate/GABA homeostasis, we provide a critical review of glutamate, glycine and GABA peptide neurotransmitters and their role in the brain, behavior, and immunity. Another aspect of maintaining this homeostasis has its origin in the gut-brain-axis which influences mood and behavior via the bidirectional biochemical exchange network between central (CNS) and enteric nervous system (ENS). This present review also provides evidence of the cross-talk between glutamate, glycine, and GABA along the microbiotagut- brain axis, thus any variations in this axis bear the consequences of the pathological condition. Drugs like alcohol, Benzodiazepines (Barbiturates) and neurosteroids inhibit the excitatory action of glutamate leading to an overall increase of glutamate/GABA ratio that causes relaxation of nerves. However, these drugs are misused and abused among drug addicts and now their commercial production is either banned or downsized and heavily monitored. Because only a limited number of drug molecules are considered in pharmaceutics and clinics as antidepressants, it is essential to focus on alternate peptide modulator analogues which are safe, eco-friendly and can be used as drugs to relieve stress and anxiety. In this review, we present a synopsis of the studies on synthetic GABAergic agonists or GABA modulators that can be targeted for future therapeutics and clinics.
... Similarly, IFN-γ, an important antiviral cytokine expressed by CD8 + T cells induced neurotoxicity by complexing the IFN-γ receptor with the AMPA glutamate receptor. Signaling through this complexed receptor via IFN-γ caused Ca 2+ influx in glutamatergic neurons and, ultimately, neuronal excitotoxicity in the form of dendritic beads [64]. ...
Flaviviruses are a family of enveloped viruses with a positive-sense RNA genome, transmitted by arthropod vectors. These viruses are known for their broad cellular tropism leading to infection of multiple body systems, which can include the central nervous system. Neurologic effects of flavivirus infection can arise during both acute and post-acute infectious periods; however, the molecular and cellular mechanisms underlying post-acute sequelae are not fully understood. Here, we review recent studies that have examined molecular and cellular mechanisms that may contribute to neurologic sequelae following infection with the West Nile virus, Japanese encephalitis virus, Zika virus, dengue virus, and St. Louis encephalitis virus. Neuronal death, either from direct infection or due to the resultant inflammatory response, is a common mechanism by which flavivirus infection can lead to neurologic impairment. Other types of cellular damage, such as oxidative stress and DNA damage, appear to be more specific to certain viruses. This article aims to highlight mechanisms of cellular damage that are common across several flavivirus members and mechanisms that are more unique to specific members. Our goal is to inspire further research to improve understanding of this area in the hope of identifying treatment options for flavivirus-associated neurologic changes.
... Moreover, dysfunctions in the regulation of glutamate levels or glutamatergic signaling are associated with disturbances in neuroplasticity mechanisms, such as the production of neurotrophic factors, memory decline, cognitive deficits, and neurotoxic events 23-26 . Although it is poorly understood, evidence pointed out that immunomodulatory event may be involved in the regulation of central glutamatergic dynamics [27][28][29] . For instance, data from murine hippocampal slices showed that high levels of INF-ɣ, TNF, and IL-1β are able to increase the expression, activity, and recruitment of postsynaptic AMPA and NMDA subunits (GluR1, NR2A/NR2B, respectively), suggesting some part of these cytokines in the physiopathology of glutamatergic transmission 28-30 . ...
Chronic consumption of hyperpalatable and hypercaloric foods has been pointed out as a factor associated with cognitive decline and memory impairment in obesity. Here, wetest the hypothesis that chronic exposure to a highly palatable diet may cause neuroinflammation,glutamatergic dysfunction, and memory impairment. For that, we exposed C57BL/6J mice to ahigh sugar and butter diet (HSB) for 12 weeks, and we investigated its effects on behavior, glialreactivity, blood–brain barrier permeability, pro‑inflammatory features, glutamatergic alterations,plasticity, and fractalkine‑CX3CR1 axis
... On the other hand, microglial activation by IFN-γ can produce nitric oxide and contribute to neurodegeneration, as well as increase compliment signaling associated with aberrant engulfment of synapses [62]. IFN-γ directly affects neurons, reducing dendrite length and impairing synapse formation [4,51,61], and can be neruotoxic [59]. IP-10/CXCL10 increases intracellular calcium levels and spontaneous activity in primary rodent neuron cultures [22,67,107]. ...
... Seahorse oxygen consumption rate measurements are displayed as mean ± standard error of the mean identify potential pathways of neuronal injury and subsequent contribution to disease. Receptors for IFN-γ, IP-10/ CXCL10, and IL-9 are found on both neurons [32,59,95,107] and astrocytes [13,31,42,117], supporting the study of their combined effect on each of these cell types. While Aβ progressive pathology signature-stimulated changes in astrocyte gene expression were limited and primarily related to immune response, we identified numerous differentially expressed genes in neurons with known AD implications, such as regulation of synapse plasticity and dendrite projection and tryptophan and mitochondrial metabolism. ...
Introduction
Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer’s disease (AD) brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in AD patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.
Methods
We used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of AD at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.
Results
We identified a pattern of up-regulated IFNγ, IP-10/CXCL10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.
Conclusions
We identify a pattern of cytokine secretion predictive of progressing amyloid-β pathology in the 5xFAD mouse model of AD that reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in AD.
... This issue was in part addressed by the same group in a subsequent publication, in which they showed that, in aging, a greater infiltration of CD8 + T cells caused the induction of interferon-responsive microglia and oligodendrocytes in the white matter [67]. In this study, the authors confirmed the deleterious effect of IFN on brain health, further indicating that microglia characterized by the expression of IFN genes might contribute to neurotoxicity [67][68][69]. A summary of microglia states described in aging is provided in Fig. 2 and a more detailed list of overlapping genes is provided in Table 1. ...
... Increased phagocytosis and lipid metabolism have been described in activated responsive microglia (ARM) [58] and white-matter-associated microglia (WAM) [65], indicating that, as described in mice, also human aged brains are characterized by an expansion of the microglia subset that present an activated phenotype and is responding to environmental perturbations, such as myelin dysfunction or amyloid-β deposition, since some of the healthy controls in human studies were non-demented subjects presenting amyloid deposition. Alongside these responsive subsets, a microglia subset defined by upregulation of IFN signaling is observed also in aged human brains, further corroborating the notion that these cells might exert a more neurotoxic role [68,69]. Nonetheless, despite these overlaps between mouse and human microglia aging phenotypes, many differences remain, underlying the importance to fully characterize mouse/human microglia phenotypes as well as use additional models that can more closely recapitulate the characteristics of human microglia in human brains. ...
Microglia are the tissue-resident macrophage population of the brain, specialized in supporting the CNS environment and protecting it from endogenous and exogenous insults. Nonetheless, their function declines with age, in ways that remain to be fully elucidated. Given the critical role played by microglia in neurodegenerative diseases, a better understanding of the aging microglia phenotype is an essential prerequisite in designing better preventive and therapeutic strategies. In this review, we discuss the most recent literature on microglia in aging, comparing findings in rodent models and human subjects.
... We studied the independent effects of our cytokine signature of AD progression on both cell types to identify potential pathways of neuronal injury and subsequent contribution to disease. Receptors for IFN-g, IP-10, and IL-9 are found on both neurons 27,53,85,97 and astrocytes, 11,26,37,107 supporting the study of their combined effect on each of these cell types. While AD signature-stimulated changes in astrocyte gene expression were limited and primarily related to immune response, we identified numerous differentially expressed genes in neurons with known AD implications, such as regulation of synapse plasticity and dendrite projection and tryptophan and mitochondrial metabolism. ...
Introduction: Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in Alzheimer's disease patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.
Methods: We used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of Alzheimer's disease at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.
Results: We identified a pattern of up-regulated IFNgamma, IP-10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.
Conclusions: An Alzheimer's disease-specific pattern of cytokine secretion reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in Alzheimer's disease.
... In this study, we compared these known pro-inflammatory substrates to the MS-relevant cytokines IL-17A and IL-10. In human neurons, IFNγ indirectly triggered neurotoxic effects mediated by astrocytes and induced direct neurotoxic effects visualized as neurite bead formation (Mizuno et al. 2008). Direct neurodegenerative effects have also been reported by TNFα in mice through silencing of survival signals (Zhao et al. 2001;Takeuchi et al. 2006). ...
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) coined by inflammation and neurodegeneration. The actual cause of the neurodegenerative component of the disease is however unclear. We investigated here the direct and differential effects of inflammatory mediators on human neurons. We used embryonic stem cell-derived (H9) human neuronal stem cells (hNSC) to generate neuronal cultures. Neurons were subsequently treated with tumour necrosis factor alpha (TNFα), interferon gamma (IFNγ), granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin 17A (IL-17A) and interleukin 10 (IL-10) separately or in combination. Immunofluorescence staining and quantitative polymerase chain reaction (qPCR) were used to assess cytokine receptor expression, cell integrity and transcriptomic changes upon treatment. H9-hNSC-derived neurons expressed cytokine receptors for IFNγ, TNFα, IL-10 and IL-17A. Neuronal exposure to these cytokines resulted in differential effects on neurite integrity parameters with a clear decrease for TNFα- and GM-CSF-treated neurons. The combinatorial treatment with IL-17A/IFNγ or IL-17A/TNFα induced a more pronounced effect on neurite integrity. Furthermore, combinatorial treatments with two cytokines induced several key signalling pathways, i.e. NFκB-, hedgehog and oxidative stress signalling, stronger than any of the cytokines alone. This work supports the idea of immune-neuronal crosstalk and the need to focus on the potential role of inflammatory cytokines on neuronal cytoarchitecture and function.
Graphical Abstract
... In their work, Mizuno et al reported the direct effect of IFN-γ on neurons; as they observed the formation of dendritic beads containing proteins from collapsed cytoskeletal structures mediating neuronal dysfunctions, without increasing cell death. 63 However, when IFN-γ is combined with pro-inflammatory cytokines, including TNF-α, the neurotoxicity is exacerbated and neurons viability decreases. 64 Coherently with these previous pieces of evidence, the neuronal inflammatory model used in the present study, that combined LPS and IFN-γ, induced an important neurotoxicity ( Figure 8). ...
Introduction
Chronic inflammation is a pernicious underlying status, well-known for its contribution to the progressive development of various diseases. In this regard, Micro-immunotherapy (MI) might be a promising therapeutic strategy. MI employs low doses (LD) and ultra-low doses (ULD) of immune regulators in their formulations. In particular, as both IL-1β and TNF-α are often used at ULD in MI medicines (MIM), a special emphasis has been made on formulations that include these factors in their compositions.
Methods
Several in vitro models have been employed in order to assess the effects of two unitary MIM consisting of ULD of IL-1β and TNF-α (u-MIM-1 and u-MIM-2, respectively), and four complex MIM (c-MIM-1, −2, −3 and −4) characterized by the presence of ULD of IL-1β and TNF-α amongst other factors. Thus, we first investigated the anti-inflammatory effects of u-MIM-1 and u-MIM-2 in a model of inflamed colon carcinoma cells. In addition, the anti-inflammatory potential of c-MIM-1, −2, −3 and −4, was assessed in in vitro models of intestinal and neuronal inflammation.
Results
The results revealed that u-MIM-1 and u-MIM-2 both induced a slight decrease in the levels of IL-1β and TNF-α transcripts. Regarding the c-MIMs’ effects, c-MIM-1 displayed the capability to restore the altered transepithelial electrical resistance in inflamed-HCoEpiC cells. Moreover, c-MIM-1 also slightly increased the expression of the junction-related protein claudin-1, both at the mRNA and protein levels. In addition, our in vitro investigations on c-MIM-2 and c-MIM-3 revealed their immune-modulatory effects in LPS-inflamed human monocytes, macrophages, and granulocytes, on the secretion of cytokines such as TNF-α, PGE2, and IL-6. Finally, c-MIM-4 restored the cell viability of LPS/IFN-γ-inflamed rat cortical neurons, while reducing the secretion of TNF-α in rat glial cells.
Discussion
Our results shed the light on the potential role of these MIM formulations in managing several chronic inflammation-related conditions.
... Importantly, CSF of ALS patients exhibits an expansion of a T cell subpopulation expressing eomesodermin, which drives IFN-expression. 32 IFN-is permeable to the blood spinal barrier, particularly in the cervical region, implying that T cells impacted by peripheral inflammation might expose motor neurons to IFN-.[33][34][35] Moreover, ...
Neuroinflammation is an established factor contributing to amyotrophic lateral sclerosis (ALS) pathology, implicating the possible detrimental effects of inflammatory cytokines to motor neurons. The RNA/DNA-binding protein TDP-43 has emerged as a pivotal actor in ALS, because TDP-43 mutations cause familial ALS and loss of nuclear TDP-43, associated with its redistribution into cytoplasmic aggregates (TDP-43 proteinopathy), in motor neurons occurs in 97% of ALS cases. However, mechanisms linking neuroinflammation to TDP-43 mis-localization have not been described. Programmed death-ligand 1 (PD-L1) is an immune-modulatory protein, highly expressed on cell surfaces following acute inflammatory stress. To determine which inflammatory cytokines might impact motor neuron function, seven cytokines known to be elevated in ALS patients cerebrospinal fluid were tested for their effects on PD-L1 expression in human iPSC-derived motor neurons. Among the tested cytokines, only interferon-gamma (IFN-gamma) was found to strongly promote PD-L1 expression. Thus, we hypothesized that excessive exposure to IFN-gamma may contribute to motor neuron degeneration in ALS. We observed that neuronal populations exposed to IFN-gamma exhibited severe TDP-43 cytoplasmic aggregation and excitotoxic behavior correlated with impaired neural firing activity, hallmarks of ALS pathology, in both normal and ALS mutant (TARDBPQ331K+/-) neurons. Single-cell RNA sequencing revealed possible mechanisms for these effects. Motor neurons exposed to IFN-gamma exhibited an extensive shift of their gene expression profile toward a neurodegenerative phenotype. Notably, IFN-gamma treatment induced aberrant expression levels for 70 genes that are listed in the recent literature as being dysregulated in ALS. Additionally, we found that genes related to neuronal electrophysiology, protein aggregation, and TDP-43 mis-regulation were abnormally expressed in IFN-gamma-treated cells. Moreover, IFN-gamma induced a significant reduction in the expression of genes that encode indispensable proteins for neuromuscular synapse development and maintenance, implying that cytokine exposure could directly impair signal transmission between motor axons and muscle membranes. Our findings suggest that IFN-gamma could be a potent upstream pathogenic driver of ALS and provide potential candidates for future therapeutic targets to treat sporadic forms of ALS, which account for roughly 90% of reported cases.
