The ectonucleotidase <i>cd39</i>/ENTPDase1 modulates purinergic‐mediated microglial migration

Färber, Katrin; Markworth, Sören; Pannasch, Ulrike; Nolte, Christiané; Prinz, Vincent; Kronenberg, Golo; Gertz, Karen; Endres, Matthias; Bechmann, Ingo; Enjyoji, Keiichi; Robson, Simon C.; Kettenmann, Helmut

doi:10.1002/glia.20606

Cited by 99 publications

(104 citation statements)

References 52 publications

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“…Moreover, the differential expression pattern of ATP-degrading enzymes (Entpd1 and Nt5e) was observed in IRF8-deficient microglia compared with wild-type microglia. Entpd1 controls the balance of ATP-adenosine and is required for ATP-induced chemotaxis of microglia [13]. In light of the increased expression of Nt5e in IRF8-deficient microglia, our results suggest that IRF8 deficiency may disrupt the ATP-ADP-adenosine balance on microglial surface, thereby impairing ATP-induced microglial chemotaxis.…”

Section: Discussionmentioning

confidence: 70%

“…Extracellular ATP is hydrolyzed by ENTPDases (e.g., ENTPdase1, which is the dominant subtype in microglia [24]) to ADP and adenosine monophosphate (AMP) [14]. ADP activates P2Y 12 Rs, which is crucial for ATP-induced microglial chemotaxis [13]. Importantly, ATP fails to induce chemotaxis in ENTPdase1-deficient microglia but rather inhibits spontaneous migratory activity [13].…”

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

“…ADP activates P2Y 12 Rs, which is crucial for ATP-induced microglial chemotaxis [13]. Importantly, ATP fails to induce chemotaxis in ENTPdase1-deficient microglia but rather inhibits spontaneous migratory activity [13]. However, the addition of a soluble ectonucleotidase restores the ability of ATP to be a chemoattractant [13].…”

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

“…Importantly, ATP fails to induce chemotaxis in ENTPdase1-deficient microglia but rather inhibits spontaneous migratory activity [13]. However, the addition of a soluble ectonucleotidase restores the ability of ATP to be a chemoattractant [13]. AMP is further hydrolyzed by NT5e to adenosine [14], resulting in the activation of microglial A3Rs and subsequently further enhancing ATP-induced microglial chemotaxis [11].…”

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

“…In addition, in vitro studies have shown that ionotropic P2X4 receptors (P2X4Rs) and adenosine A 3 receptors (A3Rs) are involved in ATP-induced chemotaxis of microglia [11,12]. Adenosine is released from cells or generated from extracellular ATP by ectonucleoside triphosphate diphosphohydrolases (ENTPDases) and ecto-5′-nucleotidase enzymes (NT5e; also known as CD73), both of which are expressed on the cell surface [13,14]. Therefore, the expression pattern of these purine receptors and even ATP-degrading enzymes may be a critical component for the ability of microglial motility.…”

Section: Introductionmentioning

confidence: 99%

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IRF8 is a transcriptional determinant for microglial motility

Masuda

Nishimoto

Tomiyama

et al. 2014

Purinergic Signalling

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Microglia, the resident immune cells of the central nervous system, are constitutively mobile cells that undergo rapid directional movement toward sites of tissue disruption. However, transcriptional regulatory mechanisms of microglial motility remain unknown. In the present study, we show that interferon regulatory factor-8 (IRF8) regulates microglial motility. We found that ATP and complement component, C5a, induced chemotaxis of IRF8 wild-type microglia. However, these responses were markedly suppressed in microglia lacking IRF8 (Irf8 −/− ). In a consistent manner, phosphorylation of Akt (which plays a crucial role in ATP-induced chemotaxis) was abolished in Irf8 −/− microglia. Real-time polymerase chain reaction analysis revealed that motility-related microglial genes such as P2Y 12 receptor were significantly suppressed in Irf8 −/− microglia. Furthermore, Irf8 −/− microglia exhibited a differential expression pattern of nucleotidedegrading enzymes compared with their wild-type counterparts. Overall, our findings suggest that IRF8 may regulate microglial motility via the control of microglial gene expression.

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Section: Discussionmentioning

confidence: 70%

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IRF8 is a transcriptional determinant for microglial motility

Masuda

Nishimoto

Tomiyama

et al. 2014

Purinergic Signalling

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Targeting miR‐155 restores abnormal microglia and attenuates disease in SOD1 mice

Butovsky

Jedrychowski

Cialic

et al. 2014

Annals of Neurology

309

285

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OBJECTIVE To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS). METHODS Nanostring microRNA, microglia and immune gene profiles, protein mass spectrometry and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice. RESULTS In SOD1 mice we found loss of the molecular signature that characterizes microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, Mafb and the upstream regulators Csf1r, Tgfb1 and Tgfbr1 which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51d in females and 27d in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes including Apoe in microglia. Treatment of adult microglia with APOE suppressed the M0-unique microglia signature and induced a M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1G93A/miR-155−/− mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes and peripheral anti-miR-155 treatment prolonged survival. INERPRETATION We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.

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Microglial zinc uptake via zinc transporters induces ATP release and the activation of microglia

Higashi

Segawa

Matsuo

et al. 2011

Glia

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Previously, we demonstrated that extracellular zinc plays a key role in transient global ischemia-induced microglial activation through sequential activation of NADPH oxidase and poly(ADP-ribose) polymerase (PARP)-1. However, it remains unclear how zinc causes the sequential activation of microglia. Here, we examined whether transporter-mediated zinc uptake is necessary for microglial activation. Administration of zinc to microglia activated them through reactive oxygen species (ROS) generation and poly(ADP-ribose) (PAR) formation, which were suppressed by intracellular zinc chelation with 25 μM TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine) or 2 μM BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester). The (65)Zn uptake by microglia was temperature- and dose-dependent, and it was blocked by metal cations, but not by L-type calcium channel blockers nifedipine and nimodipine. Expression of Zrt-Irt-like protein (ZIP)1, a plasma membrane-type zinc transporter, was detected in microglia, and nickel, a relatively sensitive substrate/inhibitor of ZIP1, showed cis- and trans-inhibitory effects on the (65)Zn uptake. Exposure of microglia to zinc increased the extracellular ATP concentration, which was suppressed by intracellular zinc chelation and inhibition of hemichannels. mRNA expression of several types of P2 receptors was detected in microglia, and periodate-oxidized ATP, a selective P2×7 receptor antagonist, attenuated the zinc-induced microglial activation via NADPH oxidase and PARP-1. Exogenous ATP and 2'(3')-O-(4-benzoyl-benzoyl) ATP also caused microglial activation through ROS generation and PAR formation. These findings demonstrate that ZIP1-mediated uptake of zinc induces ATP release and autocrine/paracrine activation of P2X(7) receptors, and then activates microglia, suggesting that zinc transporter-mediated uptake of zinc is a trigger for microglial activation via the NADPH oxidase and PARP-1 pathway. © 2011 Wiley-Liss, Inc.

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The ectonucleotidase cd39/ENTPDase1 modulates purinergic‐mediated microglial migration

Cited by 99 publications

References 52 publications

IRF8 is a transcriptional determinant for microglial motility

IRF8 is a transcriptional determinant for microglial motility

Targeting miR‐155 restores abnormal microglia and attenuates disease in SOD1 mice

Microglial zinc uptake via zinc transporters induces ATP release and the activation of microglia

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