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Astrocytes protect neurons against methylmercury via ATP/P2Y(1) receptor-mediated pathways in astrocytes.

Noguchi Y, Shinozaki Y, Fujishita K, Shibata K, Imura Y, Morizawa Y, Gachet C, Koizumi S - PLoS ONE (2013)

Bottom Line: MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6.As for the mechanism of neuro-protection by IL-6, an adenosine A1 receptor-mediated pathway in neurons seems to be involved.Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y1 receptors to upregulate IL-6, thereby leading to A1 receptor-mediated neuro-protection against MeHg.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

ABSTRACT
Methylmercury (MeHg) is a well known environmental pollutant that induces serious neuronal damage. Although MeHg readily crosses the blood-brain barrier, and should affect both neurons and glial cells, how it affects glia or neuron-to-glia interactions has received only limited attention. Here, we report that MeHg triggers ATP/P2Y1 receptor signals in astrocytes, thereby protecting neurons against MeHg via interleukin-6 (IL-6)-mediated pathways. MeHg increased several mRNAs in astrocytes, among which IL-6 was the highest. For this, ATP/P2Y1 receptor-mediated mechanisms were required because the IL-6 production was (i) inhibited by a P2Y1 receptor antagonist, MRS2179, (ii) abolished in astrocytes obtained from P2Y1 receptor-knockout mice, and (iii) mimicked by exogenously applied ATP. In addition, (iv) MeHg released ATP by exocytosis from astrocytes. As for the intracellular mechanisms responsible for IL-6 production, p38 MAP kinase was involved. MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6. As for the mechanism of neuro-protection by IL-6, an adenosine A1 receptor-mediated pathway in neurons seems to be involved. Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y1 receptors to upregulate IL-6, thereby leading to A1 receptor-mediated neuro-protection against MeHg.

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A schematic diagram, illustrating mechanisms underlying astrocyte-mediated neuro-protection against MeHg.MeHg stimulates exocytosis of astrocytic ATP that functions as both (a) autocrine and (b) paracrine signals to reveal neuro-protection, i.e., (a) the released ATP as an autocrine signal, autostimulates P2Y1 receptors to induce IL-6 that upregulates neuronal adenosine A1 receptors, (b) the released ATP from astrocytes being degraded into adenosine, stimulates neuronal adenosine A1 receptors and suppresses neuronal excitability as a paracrine signal, thereby leading to further inhibition of neuronal excitability. As for mechanisms for IL-6 synthesis and release, an increase in [Ca2+]i in astrocytes mediated by P2Y1 receptors, and subsequent p38 phosphorylation were involved (insert).
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pone-0057898-g007: A schematic diagram, illustrating mechanisms underlying astrocyte-mediated neuro-protection against MeHg.MeHg stimulates exocytosis of astrocytic ATP that functions as both (a) autocrine and (b) paracrine signals to reveal neuro-protection, i.e., (a) the released ATP as an autocrine signal, autostimulates P2Y1 receptors to induce IL-6 that upregulates neuronal adenosine A1 receptors, (b) the released ATP from astrocytes being degraded into adenosine, stimulates neuronal adenosine A1 receptors and suppresses neuronal excitability as a paracrine signal, thereby leading to further inhibition of neuronal excitability. As for mechanisms for IL-6 synthesis and release, an increase in [Ca2+]i in astrocytes mediated by P2Y1 receptors, and subsequent p38 phosphorylation were involved (insert).

Mentions: Taken together, as summarized in Figure 7, when astrocytes are exposed to MeHg, they exocytose ATP and show a neuro-protective phenotype. The released ATP functions as an autocrine to stimulate P2Y1 receptors, thereby leading to the protection of neurons against MeHg via IL-6-mediated pathways. The IL-6 increases neuronal A1 receptor expression and function. The released ATP, being metabolized into adenosine, may also function as a paracrine to exert neuro-protection via suppressing excitatory neurotransmission.


Astrocytes protect neurons against methylmercury via ATP/P2Y(1) receptor-mediated pathways in astrocytes.

Noguchi Y, Shinozaki Y, Fujishita K, Shibata K, Imura Y, Morizawa Y, Gachet C, Koizumi S - PLoS ONE (2013)

A schematic diagram, illustrating mechanisms underlying astrocyte-mediated neuro-protection against MeHg.MeHg stimulates exocytosis of astrocytic ATP that functions as both (a) autocrine and (b) paracrine signals to reveal neuro-protection, i.e., (a) the released ATP as an autocrine signal, autostimulates P2Y1 receptors to induce IL-6 that upregulates neuronal adenosine A1 receptors, (b) the released ATP from astrocytes being degraded into adenosine, stimulates neuronal adenosine A1 receptors and suppresses neuronal excitability as a paracrine signal, thereby leading to further inhibition of neuronal excitability. As for mechanisms for IL-6 synthesis and release, an increase in [Ca2+]i in astrocytes mediated by P2Y1 receptors, and subsequent p38 phosphorylation were involved (insert).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585279&req=5

pone-0057898-g007: A schematic diagram, illustrating mechanisms underlying astrocyte-mediated neuro-protection against MeHg.MeHg stimulates exocytosis of astrocytic ATP that functions as both (a) autocrine and (b) paracrine signals to reveal neuro-protection, i.e., (a) the released ATP as an autocrine signal, autostimulates P2Y1 receptors to induce IL-6 that upregulates neuronal adenosine A1 receptors, (b) the released ATP from astrocytes being degraded into adenosine, stimulates neuronal adenosine A1 receptors and suppresses neuronal excitability as a paracrine signal, thereby leading to further inhibition of neuronal excitability. As for mechanisms for IL-6 synthesis and release, an increase in [Ca2+]i in astrocytes mediated by P2Y1 receptors, and subsequent p38 phosphorylation were involved (insert).
Mentions: Taken together, as summarized in Figure 7, when astrocytes are exposed to MeHg, they exocytose ATP and show a neuro-protective phenotype. The released ATP functions as an autocrine to stimulate P2Y1 receptors, thereby leading to the protection of neurons against MeHg via IL-6-mediated pathways. The IL-6 increases neuronal A1 receptor expression and function. The released ATP, being metabolized into adenosine, may also function as a paracrine to exert neuro-protection via suppressing excitatory neurotransmission.

Bottom Line: MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6.As for the mechanism of neuro-protection by IL-6, an adenosine A1 receptor-mediated pathway in neurons seems to be involved.Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y1 receptors to upregulate IL-6, thereby leading to A1 receptor-mediated neuro-protection against MeHg.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.

ABSTRACT
Methylmercury (MeHg) is a well known environmental pollutant that induces serious neuronal damage. Although MeHg readily crosses the blood-brain barrier, and should affect both neurons and glial cells, how it affects glia or neuron-to-glia interactions has received only limited attention. Here, we report that MeHg triggers ATP/P2Y1 receptor signals in astrocytes, thereby protecting neurons against MeHg via interleukin-6 (IL-6)-mediated pathways. MeHg increased several mRNAs in astrocytes, among which IL-6 was the highest. For this, ATP/P2Y1 receptor-mediated mechanisms were required because the IL-6 production was (i) inhibited by a P2Y1 receptor antagonist, MRS2179, (ii) abolished in astrocytes obtained from P2Y1 receptor-knockout mice, and (iii) mimicked by exogenously applied ATP. In addition, (iv) MeHg released ATP by exocytosis from astrocytes. As for the intracellular mechanisms responsible for IL-6 production, p38 MAP kinase was involved. MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6. As for the mechanism of neuro-protection by IL-6, an adenosine A1 receptor-mediated pathway in neurons seems to be involved. Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y1 receptors to upregulate IL-6, thereby leading to A1 receptor-mediated neuro-protection against MeHg.

Show MeSH
Related in: MedlinePlus