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NFAT microglia

Gunjan D Manocha, Atreyi Ghatak, Kendra L Puig, Susan D Kraner, Christopher M Norris, Colin K Combs
Alzheimer's disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide...
2017: Journal of Alzheimer's Disease: JAD
Gunjan Dhawan Manocha, Angela Marie Floden, Kendra Lynn Puig, Kumi Nagamoto-Combs, Clemens R Scherzer, Colin Kelly Combs
BACKGROUND: Reactive microglia have been associated with the histological changes that occur in Parkinson's disease brains and mouse models of the disease. Multiple studies from autopsy brains have verified the presence of microgliosis in several brain regions including substantia nigra, striatum, hippocampus and various cortical areas. MPTP injections in rodents have also shown striato-nigral microgliosis correlating with the loss of dopaminergic neurons. However, consistent data with respect to cytokine and immune cell changes during Parkinson's disease have not been fully defined...
February 14, 2017: Molecular Neurodegeneration
Jiae Kim, Su-Min Kim, Jung-Min Na, Hoh-Gyu Hahn, Sung-Woo Cho, Seung-Ju Yang
We recently reported the anti-inflammatory effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on the ATP-induced activation of the NFAT and MAPK pathways through the P2X7 receptor in microglia. To further investigate the underlying mechanism of KHG26792, we studied its protective effects on hypoxia-induced toxicity in microglia. The administration of KHG26792 significantly reduced the hypoxia-induced expression and activity of caspase-3 in BV-2 microglial cells. KHG26792 also reduced hypoxia-induced inducible nitric oxide synthase protein expression, which correlated with reduced nitric oxide accumulation...
December 2016: BMB Reports
David B Kurland, Volodymyr Gerzanich, Jason K Karimy, Seung Kyoon Woo, Rudi Vennekens, Marc Freichel, Bernd Nilius, Joseph Bryan, J Marc Simard
BACKGROUND: Harmful effects of activated microglia are due, in part, to the formation of peroxynitrite radicals, which is attributable to the upregulation of inducible nitric oxide (NO) synthase (NOS2). Because NOS2 expression is determined by Ca(2+)-sensitive calcineurin (CN) dephosphorylating nuclear factor of activated T cells (NFAT), and because Sur1-Trpm4 channels are crucial for regulating Ca(2+) influx, we hypothesized that, in activated microglia, Sur1-Trpm4 channels play a central role in regulating CN/NFAT and downstream target genes such as Nos2...
June 1, 2016: Journal of Neuroinflammation
Jennifer L Furman, Pradoldej Sompol, Susan D Kraner, Melanie M Pleiss, Esther J Putman, Jacob Dunkerson, Hafiz Mohmmad Abdul, Kelly N Roberts, Stephen W Scheff, Christopher M Norris
UNLABELLED: Increasing evidence suggests that the calcineurin (CN)-dependent transcription factor NFAT (Nuclear Factor of Activated T cells) mediates deleterious effects of astrocytes in progressive neurodegenerative conditions. However, the impact of astrocytic CN/NFAT signaling on neural function/recovery after acute injury has not been investigated extensively. Using a controlled cortical impact (CCI) procedure in rats, we show that traumatic brain injury is associated with an increase in the activities of NFATs 1 and 4 in the hippocampus at 7 d after injury...
February 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Eun-A Kim, Chang Hun Cho, Jiae Kim, Hoh-Gyu Hahn, Soo Young Choi, Seung-Ju Yang, Sung-Woo Cho
Azetidine derivatives are of interest for drug development because they may be useful therapeutic agents. However, their mechanisms of action remain to be completely elucidated. Here, we have investigated the effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on ATP-induced activation of NFAT and MAPK through P2X7 receptor in the BV-2 mouse microglial cell line. KHG26792 decreased ATP-induced TNF-α release from BV-2 microglia by suppressing, at least partly, P2X7 receptor stimulation...
December 2015: Neurotoxicology
Bo Ma, Jia Yu, Chengsong Xie, Lixin Sun, Shannon Lin, Jinhui Ding, Jing Luo, Huaibin Cai
UNLABELLED: Microglia are resident macrophages in the CNS that scavenge pathogens, dying cells, and molecules using pattern recognition Toll-like receptors (TLRs). Nuclear factor of activated T-cells (NFAT) family transcription factors also regulate inflammatory responses in microglia. However, whether there exists cross talk between TLR and NFAT signaling is unclear. Here we show that chronic activation of murine microglia by prolonged stimulation of Toll-like receptor 4 (TLR4) ligand lipopolysaccharides (LPSs) leads to unexpected translocation of NFAT1 into mitochondria...
July 29, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
David B Kurland, Jesse Stokum, Alex Ivanov, Volodymyr Gerzanich, J Marc Simard
INTRODUCTION: Microglia, the resident immune cells of the central nervous system, play a critical role in health and disease. Following injury, microglia upregulate inducible nitric oxide synthase (iNOS), and can exert neurotoxic effects by releasing large quantities of nitric oxide (NO). Expression of iNOS, and many other proinflammatory genes, is regulated in part by Ca influx and Ca-dependent transcription factors. The expression of the nonselective cation channel Sur1-Trpm4 may be 1 molecular mechanism by which microglia dynamically modulate Ca influx...
August 2015: Neurosurgery
Sung-Dong Park, So Yeong Cheon, Tae-Yoon Park, Bo-Young Shin, Hyunju Oh, Sankar Ghosh, Bon-Nyeo Koo, Sang-Kyou Lee
Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex...
August 28, 2015: Biochemical and Biophysical Research Communications
Lalida Rojanathammanee, Angela M Floden, Gunjan D Manocha, Colin K Combs
BACKGROUND: Amyloid β (Aβ) peptide is hypothesized to stimulate microglia to acquire their characteristic proinflammatory phenotype in Alzheimer's disease (AD) brains. The specific mechanisms by which Aβ leads to microglial activation remain an area of interest for identifying attractive molecular targets for intervention. Based upon the fact that microglia express the proinflammatory transcription factor, nuclear factor of activated T cells (NFAT), we hypothesized that NFAT activity is required for the Aβ-stimulated microgliosis that occurs during disease...
2015: Journal of Neuroinflammation
Lalida Rojanathammanee, Angela M Floden, Gunjan D Manocha, Colin K Combs
BACKGROUND: Amyloid β (Aβ) peptide is hypothesized to stimulate microglia to acquire their characteristic proinflammatory phenotype in Alzheimer's disease (AD) brains. The specific mechanisms by which Aβ leads to microglial activation remain an area of interest for identifying attractive molecular targets for intervention. Based upon the fact that microglia express the proinflammatory transcription factor, nuclear factor of activated T cells (NFAT), we hypothesized that NFAT activity is required for the Aβ-stimulated microgliosis that occurs during disease...
December 2015: Journal of Neuroinflammation
Dmitri Lodygin, Francesca Odoardi, Christian Schläger, Henrike Körner, Alexandra Kitz, Michail Nosov, Jens van den Brandt, Holger M Reichardt, Michael Haberl, Alexander Flügel
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific nervous antigens. When and where the disease-relevant antigen encounters occur is unclear. Here we combined fluorescently labeled nuclear factor of activated T cells (NFAT) with histone protein H2B to create a broadly applicable molecular sensor for intravital imaging of T cell activation. In experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, we report that effector T cells entering the CNS become activated after short contacts with leptomeningeal phagocytes...
June 2013: Nature Medicine
Lalida Rojanathammanee, Kendra L Puig, Colin K Combs
Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6...
May 2013: Journal of Nutrition
Seth M Dever, Ruqiang Xu, Sylvia Fitting, Pamela E Knapp, Kurt F Hauser
The μ-opioid receptor (MOR) is known to undergo extensive alternative splicing as numerous splice variants of MOR have been identified. However, the functional significance of MOR variants, as well as how splice variants other than MOR-1 might differentially regulate human immunodeficiency virus type-1 (HIV-1) pathogenesis in the central nervous system (CNS), or elsewhere, has largely been ignored. Our findings suggest that there are specific differences in the MOR variant expression profile among CNS cell types, and that the expression levels of these variants are differentially regulated by HIV-1...
June 2012: Journal of Neurovirology
Rei Yamaguchi, Masahiro Hosaka, Seiji Torii, Ni Hou, Nobuhito Saito, Yuhei Yoshimoto, Hideaki Imai, Toshiyuki Takeuchi
Experimental cerebral ischemia has been reportedly alleviated by the immunosuppressive agent cyclosporin A (CsA). Cyclophilin C-associated protein (CyCAP) was proposed to be an endogenous equivalent of CsA; CsA- and CyCAP-targeting protein cyclophilin C have attracted extensive attention regarding their ischemia-alleviating mechanisms. In this study we have introduced the specific CyCAP antibody for evaluating its distribution in the rat ischemic brain after middle cerebral artery occlusion. During the recovery of cerebral ischemia in rats, CyCAP was highly expressed in the activated microglia/macrophages in the ischemic lesion...
June 23, 2011: Brain Research
Beomsue Kim, Hey-kyeong Jeong, Jong-hyeon Kim, Sang Yoon Lee, Ilo Jou, Eun-hye Joe
Chemokines play critical roles in inflammation by recruiting inflammatory cells to injury sites. In this study, we found that UDP induced expression of chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) in microglia, astrocytes, and slice cultures by activation of P2Y(6). Interestingly, CCL2 was more highly expressed than CCL3. However, CCL2 synthesis kinetics in response to UDP differed in microglia and astrocytes; microglia rapidly produced small amounts of CCL2, whereas astrocytes continuously synthesized large amounts of CCL2, resulting in a high ultimate level of the chemokine...
March 15, 2011: Journal of Immunology: Official Journal of the American Association of Immunologists
María C Serrano-Pérez, Eduardo D Martín, Cecilia F Vaquero, Iñigo Azcoitia, Soledad Calvo, Eva Cano, Pedro Tranque
Astrocytes react to brain injury triggering neuroinflammatory processes that determine the degree of neuronal damage. However, the signaling events associated to astrocyte activation remain largely undefined. The nuclear factor of activated T-cells (NFAT) is a transcription factor family implicated in activation of immune cells. We previously characterized the expression of NFAT isoforms in cultured astrocytes, and NFAT activation in response to mechanical lesion. Here we analyze NFATc3 in two mouse models of inflammatory brain damage: hippocampal excitotoxicity induced by intracerebral kainic acid (KA) injection and cortical mechanical lesion...
January 2011: Glia
Kumi Nagamoto-Combs, Colin K Combs
The transcription factor family, nuclear factor of activated T cells (NFAT), regulates immune cell phenotype. Four different calcium/calmodulin-regulated isoforms have been identified in the periphery, but isoform expression in microglia, the resident immune cells of the CNS, has not been fully defined. In this study microglial NFAT isoform expression and involvement in regulating inflammatory responses in murine primary microglia culture was examined. Western blot analysis demonstrated robust detection of NFATc1 and c2 isoforms in microglia...
July 14, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Miho Shiratori, Hidetoshi Tozaki-Saitoh, Mai Yoshitake, Makoto Tsuda, Kazuhide Inoue
Microglia plays an important role in many neurodegenerative conditions. ATP leaked or released by damaged cells triggers microglial activation through P2 receptors, and stimulates the release of oxygen radicals, proinflammatory cytokines and chemokines from activated microglia. However, little is known about mechanisms underlying ATP-induced chemokine release from microglia. In this study, we found that a high concentration of ATP induces the mRNA expression and release of CXCL2 from microglia. A similar effect was observed following treatment of microglia with a P2X7 receptor (P2X7R) agonist, 2'-and 3'-O-(4-benzoylbenzoyl) ATP, and this was inhibited by pre-treatment with a P2X7R antagonist, Brilliant Blue G...
August 2010: Journal of Neurochemistry
Ayako Kataoka, Hidetoshi Tozaki-Saitoh, Yui Koga, Makoto Tsuda, Kazuhide Inoue
Microglia are implicated as a source of diverse proinflammatory factors in the CNS. Extracellular nucleotides are well known to be potent activators of glial cells and trigger the release of cytokines from microglia through purinergic receptors. However, little is known about the role of purinoceptors in microglial chemokine release. In this study, we found that high concentrations of ATP evoked release of CC-chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1alpha from MG-5 cells, a mouse microglial cell line, and rapid up-regulation of CCL3 mRNA was elicited within 30 min of ATP stimulation...
January 2009: Journal of Neurochemistry
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