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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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Neuro-protection by astrocyte-derived IL-6.(A) The experimental schedule. MeHg (1 or 3 µM) was treated to the astrocyte culture for 24 h and the ACM was transferred into the neuronal culture. The ACM-treated neuronal cultures were further incubated for 48 h with or without IL-6 antibody. (B) ACM restored the reduction in neuronal viability evoked by MeHg (1 or 3 µM, 48 hr). The ACM-induced neuro-protection against MeHg was significantly reduced by IL-6 antibody (100 ng/ml). **P<0.01 vs. MeHg.
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pone-0057898-g005: Neuro-protection by astrocyte-derived IL-6.(A) The experimental schedule. MeHg (1 or 3 µM) was treated to the astrocyte culture for 24 h and the ACM was transferred into the neuronal culture. The ACM-treated neuronal cultures were further incubated for 48 h with or without IL-6 antibody. (B) ACM restored the reduction in neuronal viability evoked by MeHg (1 or 3 µM, 48 hr). The ACM-induced neuro-protection against MeHg was significantly reduced by IL-6 antibody (100 ng/ml). **P<0.01 vs. MeHg.

Mentions: We then examined the neuro-protective effect of astrocyte-conditioned medium (ACM, MeHg-treated astrocytes conditioned medium). As shown in figure 5A, astrocytes were incubated with MeHg (1 or 3 µM, 24 hr) and ACM was transferred into neuronal culture and neurons were further incubated in the either presence or absence of anti-IL-6 antibody (100 ng/ml) for 48 hr. ACM restored the MeHg-decreased neuronal viability (1 µM MeHg, 41.8±3.0%; 1 µM MeHg/ACM, 70.6±2.9%; 3 µM MeHg, 18.9±2.0%; 3 µM MeHg/ACM, 52.3±4.0%, n = 30) (Fig. 5B). The protective effects of ACM were abolished by IL-6 antibody (1 µM MeHg/ACM/IL-6 Ab, 47.4±4.3%; 3 µM MeHg/ACM/IL-6 Ab, 35.5±3.1%, n = 15), indicating that the ACM-mediated neuro-protection is dependent on IL-6. IL-6 antibody itself showed no direct effect on neuronal cell viability (97.7±9.8%; n = 5). When IL-6 was added to neurons 12 hr after MeHg, it no longer showed neuro-protection (1 µM of MeHg, 57.0±6.4%; MeHg/IL-6, 64.6±8.0%, n = 6, P>0.05), suggesting that an effective time window seems to be present for the IL-6- or ACM-mediated neuro-protection.


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)

Neuro-protection by astrocyte-derived IL-6.(A) The experimental schedule. MeHg (1 or 3 µM) was treated to the astrocyte culture for 24 h and the ACM was transferred into the neuronal culture. The ACM-treated neuronal cultures were further incubated for 48 h with or without IL-6 antibody. (B) ACM restored the reduction in neuronal viability evoked by MeHg (1 or 3 µM, 48 hr). The ACM-induced neuro-protection against MeHg was significantly reduced by IL-6 antibody (100 ng/ml). **P<0.01 vs. MeHg.
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Related In: Results  -  Collection

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

pone-0057898-g005: Neuro-protection by astrocyte-derived IL-6.(A) The experimental schedule. MeHg (1 or 3 µM) was treated to the astrocyte culture for 24 h and the ACM was transferred into the neuronal culture. The ACM-treated neuronal cultures were further incubated for 48 h with or without IL-6 antibody. (B) ACM restored the reduction in neuronal viability evoked by MeHg (1 or 3 µM, 48 hr). The ACM-induced neuro-protection against MeHg was significantly reduced by IL-6 antibody (100 ng/ml). **P<0.01 vs. MeHg.
Mentions: We then examined the neuro-protective effect of astrocyte-conditioned medium (ACM, MeHg-treated astrocytes conditioned medium). As shown in figure 5A, astrocytes were incubated with MeHg (1 or 3 µM, 24 hr) and ACM was transferred into neuronal culture and neurons were further incubated in the either presence or absence of anti-IL-6 antibody (100 ng/ml) for 48 hr. ACM restored the MeHg-decreased neuronal viability (1 µM MeHg, 41.8±3.0%; 1 µM MeHg/ACM, 70.6±2.9%; 3 µM MeHg, 18.9±2.0%; 3 µM MeHg/ACM, 52.3±4.0%, n = 30) (Fig. 5B). The protective effects of ACM were abolished by IL-6 antibody (1 µM MeHg/ACM/IL-6 Ab, 47.4±4.3%; 3 µM MeHg/ACM/IL-6 Ab, 35.5±3.1%, n = 15), indicating that the ACM-mediated neuro-protection is dependent on IL-6. IL-6 antibody itself showed no direct effect on neuronal cell viability (97.7±9.8%; n = 5). When IL-6 was added to neurons 12 hr after MeHg, it no longer showed neuro-protection (1 µM of MeHg, 57.0±6.4%; MeHg/IL-6, 64.6±8.0%, n = 6, P>0.05), suggesting that an effective time window seems to be present for the IL-6- or ACM-mediated neuro-protection.

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