P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways

Shiratori, Miho; Saitoh, Hidetoshi; Yoshitake, Mai; Tsuda, Makoto; Inoue, Kazuhide

doi:10.1016/j.neures.2010.07.1057

Cited by 35 publications

(47 citation statements)

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“…A number of groups have shown that ATP and other nucleotides can elicit transient or sustained Ca 2+ signals in a variety of other cell types (Oshimi et al, 1999;Möller et al, 2000;Nobile et al, 2003;Korcok et al, 2004). The role of the Ca 2+ -regulated NFAT transcription factors in P2 receptor signaling has also been examined previously (Ferrari et al, 1999;Abbott et al, 2000;Kataoka et al, 2009;Shiratori et al, 2010). However, no previous studies have employed a concentration range capable of revealing the relationship between ATP dose and Ca 2+ -NFAT signal duration described in the present study.…”

Section: P2 Receptor Network Enable Dose-to-duration Encoding Of Ca mentioning

confidence: 75%

P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations

Grol

Pereverzev²,

Sims³

et al. 2013

Journal of Cell Science

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SummaryThe primordial intercellular signaling molecule ATP acts through two families of cell-surface P2 receptors -the P2Y family of Gprotein-coupled receptors and the P2X family of ligand-gated cation channels. Multiple P2 receptors are expressed in a variety of cell types. However, the significance of these networks of receptors in any biological system remains unknown. Using osteoblasts as a model system, we found that a low concentration of ATP (10 mM, ATP low ) induced transient elevation of cytosolic Ca 2+ , whereas a high concentration of ATP (1 mM, ATP high ) elicited more sustained elevation. Moreover, graded increases in the Ca 2+ signal were achieved over a remarkable million-fold range of ATP concentrations (1 nM to 1 mM). Next, we demonstrated that ATP low caused transient nuclear localization of the Ca 2+ -regulated transcription factor NFATc1; whereas, ATP high elicited more sustained localization. When stimulated with ATP high , osteoblasts from P2X7 loss-of-function mice showed only transient Ca 2+ -NFATc1 signaling; in contrast, sustained signaling was observed in wild-type cells. Additional experiments revealed a role for P2Y receptors in mediating transient signaling induced by low ATP concentrations. Thus, distinct P2 receptors with varying affinities for ATP account for this wide range of sensitivity to extracellular nucleotides. Finally, ATP high , but not ATP low , was shown to elicit robust expression of the NFAT target gene Ptgs2 (encoding COX-2), consistent with a crucial role for the duration of Ca 2+ -NFAT signaling in regulating target gene expression. Taken together, ensembles of P2 receptors provide a mechanism by which cells sense ATP over a wide concentration range and transduce this input into distinct cellular signals.

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Section: P2 Receptor Network Enable Dose-to-duration Encoding Of Ca mentioning

confidence: 75%

P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations

Grol

Pereverzev²,

Sims³

et al. 2013

Journal of Cell Science

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“…CXCL2 has chemotactic properties similar to those of CXCL1, recruiting neutrophils to sites of infection or injury (5,20,35). Interestingly, in contrast to CXCL1, CXCL2 expression progressively increased out to day 7 postinfection and steadily declined thereafter (Fig.…”

Section: Fig 4 Catheter-associated Bacterial Growth Is Significantly mentioning

confidence: 89%

Biofilm-Infected Intracerebroventricular Shunts Elicit Inflammation within the Central Nervous System

et al. 2012

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ABSTRACTCentral nervous system catheter infections are a serious complication in the treatment of hydrocephalus. These infections are commonly caused byStaphylococcus epidermidisandStaphylococcus aureus, both known to form biofilms on the catheter surface. Our objective was to generate a novel murine model of central nervous system catheter-associated biofilm infection using a clinicalS. aureusisolate and characterize the nature of the inflammatory response during biofilm growth. Silicone catheters were precoated withS. aureusto facilitate bacterial attachment, whereupon infected or sterile catheters were stereotactically inserted into the lateral ventricle of the brain in C57BL/6 mice and evaluated at regular intervals through day 21 postinsertion. Animals tolerated the procedure well, with no clinical signs of illness or bacterial growth seen in the control group. Bacterial titers associated with central nervous system catheters were significantly elevated compared to those from the surrounding parenchyma, consistent with biofilm formation and minimal planktonic spread of infection. Catheter-associated bacterial burdens progressively increased, with maximal colonization achieved at day 7 postinfection. Analysis of inflammatory infiltrates by fluorescence-activated cell sorting (FACS) revealed significant macrophage and neutrophil influx, which peaked at days 3 and 5 to 7, respectively. In contrast, there were no detectable immune infiltrates associated with tissues surrounding sterile catheters. Biofilm infection led to significant increases in chemokine (CXCL1 and CCL2) and proinflammatory cytokine (interleukin 17 [IL-17]) expression in tissues surrounding infected central nervous system catheters. Based on these results, we propose this approach is a valid animal model for further investigations of catheter-associated central nervous system shunt infections.

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“…The stimulation of P2X 7 receptors in primary microglia upregulated synthesis and induced release of CCchemokine ligand 3 (CCL3)/macrophage inflammatory protein-1␣; this release was blocked by P2X 7 receptor antagonists and selective inhibition of nuclear factor activated T cells (NFAT) (435). Similarly, P2X 7 receptor activation increases expression and induces the release of CXCL2 chemokine from rat cultured microglia via NFAT and MAPKs (p38, ERK, and JNK) signaling cascades (830). P2X 7 receptor-mediated Ca 2ϩ influx was shown to suppress the synthesis of microglial response factor-1 gene (mrf-1; the latter being the part of microglial activation induced by neuronal death in vitro and in vivo) at the transcriptional level (440).…”

Section: P2x 7 Receptors and Microglial Functionmentioning

confidence: 99%

Physiology of Microglia

Kettenmann

Hanisch

Нода

et al. 2011

Physiological Reviews

3,101

2,981

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Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

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P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways

Cited by 35 publications

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P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations

P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations

Biofilm-Infected Intracerebroventricular Shunts Elicit Inflammation within the Central Nervous System

Physiology of Microglia

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