Phagocytosis is Regulated by Nitric Oxide in Murine Microglia

Kopec, Karla; Carroll, Richard T.

doi:10.1006/niox.2000.0280

Cited by 40 publications

(24 citation statements)

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“…It has been reported that microglia continue to produce pro-inflammatory cytokines but lose their Aβ clearance capabilities in a PS1-APP transgenic mouse model of AD [50]. Treatment with NO-generating compounds caused impaired phagocytosis in BV-2 microglia, and an inverse correlation between NO production and phagocytosis was observed upon β-amyloid pretreatment [51]. The addition of TNF-α reduces the expression of Aβ phagocytosis-related genes and decreases the uptake of Aβ in N9 cells [50].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of STAT3- and MAPK-dependent PGE2 synthesis ameliorates phagocytosis of fibrillar β-amyloid peptide (1-42) via EP2 receptor in EMF-stimulated N9 microglial cells

Luo

Shen

et al. 2016

J Neuroinflammation

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BackgroundProstaglandin E2 (PGE2)-involved neuroinflammatory processes are prevalent in several neurological conditions and diseases. Amyloid burden is correlated with the activation of E-prostanoid (EP) 2 receptors by PGE2 in Alzheimer’s disease. We previously demonstrated that electromagnetic field (EMF) exposure can induce pro-inflammatory responses and the depression of phagocytosis in microglial cells, but the signaling pathways involved in phagocytosis of fibrillar β-amyloid (fAβ) in microglial cells exposed to EMF are poorly understood. Given the important role of PGE2 in neural physiopathological processes, we investigated the PGE2-related signaling mechanism in the immunomodulatory phagocytosis of EMF-stimulated N9 microglial cells (N9 cells).MethodsN9 cells were exposed to EMF with or without pretreatment with the selective inhibitors of cyclooxygenase-2 (COX-2), Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs) and antagonists of PG receptors EP1-4. The production of endogenous PGE2 was quantified by enzyme immunoassays. The phagocytic ability of N9 cells was evaluated based on the fluorescence intensity of the engulfed fluorescent-labeled fibrillar β-amyloid peptide (1-42) (fAβ42) measured using a flow cytometer and a fluorescence microscope. The effects of pharmacological agents on EMF-activated microglia were investigated based on the expressions of JAK2, STAT3, p38/ERK/JNK MAPKs, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1), and EP2 using real-time PCR and/or western blotting.ResultsEMF exposure significantly increased the production of PGE2 and decreased the phagocytosis of fluorescent-labeled fAβ42 by N9 cells. The selective inhibitors of COX-2, JAK2, STAT3, and MAPKs clearly depressed PGE2 release and ameliorated microglial phagocytosis after EMF exposure. Pharmacological agents suppressed the phosphorylation of JAK2-STAT3 and MAPKs, leading to the amelioration of the phagocytic ability of EMF-stimulated N9 cells. Antagonist studies of EP1-4 receptors showed that EMF depressed the phagocytosis of fAβ42 through the PGE2 system, which is linked to EP2 receptors.ConclusionsThis study indicates that EMF exposure could induce phagocytic depression via JAK2-STAT3- and MAPK-dependent PGE2-EP2 receptor signaling pathways in microglia. Therefore, pharmacological inhibition of PGE2 synthesis and EP2 receptors may be a potential therapeutic strategy to combat the neurobiological deterioration that follows EMF exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0762-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Inhibition of STAT3- and MAPK-dependent PGE2 synthesis ameliorates phagocytosis of fibrillar β-amyloid peptide (1-42) via EP2 receptor in EMF-stimulated N9 microglial cells

Luo

Shen

et al. 2016

J Neuroinflammation

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“…BV-2 cells have been shown to avidly ingest 1-m fluorescent microspheres by phagocytosis (22,32). Surprisingly, uptake of microspheres was not enhanced by M-CSFR overexpression.…”

Section: Discussionmentioning

confidence: 99%

Accelerated Phagocytosis of Amyloid-β by Mouse and Human Microglia Overexpressing the Macrophage Colony-stimulating Factor Receptor

Mitrasinovic

Murphy

2002

Journal of Biological Chemistry

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Alzheimer's disease (AD) 1 is characterized by amyloid-␤ peptide (A␤) plaques surrounded by microglia. A␤ is thought to be directly neurotoxic, and activated microglia are hypothesized to have negative effects on neurons through the release of effectors of inflammation (1). However, as brain macrophages microglia can clear A␤ by phagocytosis, primarily through macrophage scavenger receptors (MSR) (2-6). Immunization of transgenic mice modeling AD with A␤ results in clearance of plaques from the brain (7). Whereas some results suggest that microglial phagocytosis may be key in clearance of A␤ after immunization (8), other findings indicate that circulating antibodies may result in movement of A␤ out of the brain (9). This controversy has stimulated renewed interest in uptake of A␤ by microglia.A distinctive phenotypic feature of microglia surrounding A␤ plaques in APPV717F transgenic mice and in AD is enhanced expression of the macrophage colony-stimulating factor receptor (M-CSFR), translation product of the c-fms proto-oncogene (10, 11). Microglial M-CSFR expression is also increased after experimental ischemic and traumatic brain injury (12, 13). M-CSFR regulates proliferation, activation, and survival of cells in the monocyte-macrophage lineage through tyrosine kinase activation of diverse signal transduction pathways including: Src kinase, Ras-ERK, phosphoinositide 3-kinase, and p38 MAP kinase (14 -16). Deletion of M-CSFR expression results in decreased numbers of cells of the mononuclear phagocyte lineage (17). In AD macrophage colony-stimulating factor (M-CSF), the ligand for M-CSFR expressed by neurons and glia is also increased (18). Simultaneous increases in M-CSF and M-CSFR expression in the brain could result in significant changes in microglial function.We recently demonstrated that overexpression of M-CSFR by cultured microglia increases proliferation, stimulates release of pro-inflammatory and chemotactic cytokines, and induces a paracrine inflammatory response in a microglial-organotypic co-culture system (19). In the present study we sought to determine the effects of M-CSFR overexpression on A␤ phagocytosis by cultured mouse and human microglia. We hypothesized that M-CSFR-induced activation of microglia would increase their capacity to clear A␤ from culture medium. Although A␤ immunization clinical trials have been discontinued in humans for the present, identifying factors that enhance microglial clearance of A␤ may be of benefit in devising alternative means of decreasing A␤ burden in the brain in AD. EXPERIMENTAL PROCEDURES Microglial Cell Lines, Plasmid Transfections, and Tissue culture-The c-fms expression plasmid pTK1 was a gift from Dr. Rao Tekmal (Emory University, Atlanta, GA), and contains the complete mouse c-fms sequence under the control of an SV40 promoter (20). Transfections were carried out using mouse BV-2 and human SV-A3 microglial cells. The BV-2 immortalized microglial cell line has been characterized previously (21)(22)(23)(24). Because of phenotypic changes that occur at...

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“…In vitro cultures of wild-type microglia seem to be more activated than those of PrP 0/0 microglia because of augmented production of superoxide after stimulation with LPS or concanavalin A [160] and PrP [161], and also of nitrite after stimulation with the PrP peptide PrP 106-126 [161]. Phagocytosis is negatively modulated by superoxide [162] and the superoxide derivative H 2 O 2 [163][164][165][166] (but see [167]), as well as nitric oxide [168][169][170] and its derivative, nitrite [171]. These data are consistent with the observation of higher phagocytic activity in PrP 0/0 macrophages [156].…”

Section: Prp C a Novel Negative Modulator Of Phagocytosismentioning

confidence: 97%

Phagocytosis of apoptotic cells: a matter of balance

Almeida

Linden

2005

CMLS, Cell. Mol. Life Sci.

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Efficient clearance of apoptotic cells is required to control homeostasis in normal and pathological circumstances, and inappropriate clearance of cell corpses may lead to autoimmune diseases and inflammation. The multiplicity of phagocytotic mechanisms points to the relevance of removing apoptotic cells. A variety of surface molecules present in either the apoptotic bodies or phagocytes help in attachment and initiation of engulfment. Nonetheless, uncontrolled phagocytosis of apoptotic cells and other particles may lead to tissue injury; therefore, negative signals are important in balancing phagocytotic activity. This review aims at a systematic examination of positive and negative signals that modulate the uptake of apoptotic bodies and the signaling mechanisms involved in the clearance of apoptotic cells.

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Phagocytosis is Regulated by Nitric Oxide in Murine Microglia

Cited by 40 publications

References 39 publications

Inhibition of STAT3- and MAPK-dependent PGE2 synthesis ameliorates phagocytosis of fibrillar β-amyloid peptide (1-42) via EP2 receptor in EMF-stimulated N9 microglial cells

Inhibition of STAT3- and MAPK-dependent PGE2 synthesis ameliorates phagocytosis of fibrillar β-amyloid peptide (1-42) via EP2 receptor in EMF-stimulated N9 microglial cells

Accelerated Phagocytosis of Amyloid-β by Mouse and Human Microglia Overexpressing the Macrophage Colony-stimulating Factor Receptor

Phagocytosis of apoptotic cells: a matter of balance

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