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GABA A receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β
Gangliogliomas (GGs) are low-grade brain tumours that cause intractable focal epilepsy in children and adults. In GG, as in epileptogenic focal malformations (i.e., tuberous sclerosis complex, TSC), there is evidence of sustained neuroinflammation with involvement of the pro-inflammatory cytokine IL...
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Published in: | Scientific reports 2022-10, Vol.12 (1), p.17956 |
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creator | Ruffolo, Gabriele Alfano, Veronica Romagnolo, Alessia Zimmer, Till Mills, James D Cifelli, Pierangelo Gaeta, Alessandro Morano, Alessandra Anink, Jasper Mühlebner, Angelika Vezzani, Annamaria Aronica, Eleonora Palma, Eleonora |
description | Gangliogliomas (GGs) are low-grade brain tumours that cause intractable focal epilepsy in children and adults. In GG, as in epileptogenic focal malformations (i.e., tuberous sclerosis complex, TSC), there is evidence of sustained neuroinflammation with involvement of the pro-inflammatory cytokine IL-1β. On the other hand, anti-inflammatory mediators are less studied but bear relevance for understanding seizure mechanisms. Therefore, we investigated the effect of the key anti-inflammatory cytokine IL-10 on GABAergic neurotransmission in GG. We assessed the IL-10 dependent signaling by transcriptomic analysis, immunohistochemistry and performed voltage-clamp recordings on Xenopus oocytes microtransplanted with cell membranes from brain specimens, to overcome the limited availability of acute GG slices. We report that IL-10-related mRNAs were up-regulated in GG and slightly in TSC. Moreover, we found IL-10 receptors are expressed by neurons and astroglia. Furthermore, GABA currents were potentiated significantly by IL-10 in GG. This effect was time and dose-dependent and inhibited by blockade of IL-10 signaling. Notably, in the same tissue, IL-1β reduced GABA current amplitude and prevented the IL-10 effect. These results suggest that in epileptogenic tissue, pro-inflammatory mechanisms of hyperexcitability prevail over key anti-inflammatory pathways enhancing GABAergic inhibition. Hence, boosting the effects of specific anti-inflammatory molecules could resolve inflammation and reduce intractable seizures. |
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In GG, as in epileptogenic focal malformations (i.e., tuberous sclerosis complex, TSC), there is evidence of sustained neuroinflammation with involvement of the pro-inflammatory cytokine IL-1β. On the other hand, anti-inflammatory mediators are less studied but bear relevance for understanding seizure mechanisms. Therefore, we investigated the effect of the key anti-inflammatory cytokine IL-10 on GABAergic neurotransmission in GG. We assessed the IL-10 dependent signaling by transcriptomic analysis, immunohistochemistry and performed voltage-clamp recordings on Xenopus oocytes microtransplanted with cell membranes from brain specimens, to overcome the limited availability of acute GG slices. We report that IL-10-related mRNAs were up-regulated in GG and slightly in TSC. Moreover, we found IL-10 receptors are expressed by neurons and astroglia. Furthermore, GABA currents were potentiated significantly by IL-10 in GG. This effect was time and dose-dependent and inhibited by blockade of IL-10 signaling. Notably, in the same tissue, IL-1β reduced GABA current amplitude and prevented the IL-10 effect. These results suggest that in epileptogenic tissue, pro-inflammatory mechanisms of hyperexcitability prevail over key anti-inflammatory pathways enhancing GABAergic inhibition. Hence, boosting the effects of specific anti-inflammatory molecules could resolve inflammation and reduce intractable seizures.</description><identifier>EISSN: 2045-2322</identifier><identifier>PMID: 36289354</identifier><language>eng</language><publisher>England</publisher><subject>Adult ; Child ; Drug Resistant Epilepsy ; gamma-Aminobutyric Acid ; Ganglioglioma - complications ; Humans ; Interleukin-10 - metabolism ; Interleukin-1beta - metabolism ; Receptors, GABA-A - metabolism ; Receptors, Immunologic - metabolism ; Receptors, Interleukin-10 - metabolism</subject><ispartof>Scientific reports, 2022-10, Vol.12 (1), p.17956</ispartof><rights>2022. 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In GG, as in epileptogenic focal malformations (i.e., tuberous sclerosis complex, TSC), there is evidence of sustained neuroinflammation with involvement of the pro-inflammatory cytokine IL-1β. On the other hand, anti-inflammatory mediators are less studied but bear relevance for understanding seizure mechanisms. Therefore, we investigated the effect of the key anti-inflammatory cytokine IL-10 on GABAergic neurotransmission in GG. We assessed the IL-10 dependent signaling by transcriptomic analysis, immunohistochemistry and performed voltage-clamp recordings on Xenopus oocytes microtransplanted with cell membranes from brain specimens, to overcome the limited availability of acute GG slices. We report that IL-10-related mRNAs were up-regulated in GG and slightly in TSC. Moreover, we found IL-10 receptors are expressed by neurons and astroglia. Furthermore, GABA currents were potentiated significantly by IL-10 in GG. This effect was time and dose-dependent and inhibited by blockade of IL-10 signaling. Notably, in the same tissue, IL-1β reduced GABA current amplitude and prevented the IL-10 effect. These results suggest that in epileptogenic tissue, pro-inflammatory mechanisms of hyperexcitability prevail over key anti-inflammatory pathways enhancing GABAergic inhibition. Hence, boosting the effects of specific anti-inflammatory molecules could resolve inflammation and reduce intractable seizures.</description><subject>Adult</subject><subject>Child</subject><subject>Drug Resistant Epilepsy</subject><subject>gamma-Aminobutyric Acid</subject><subject>Ganglioglioma - complications</subject><subject>Humans</subject><subject>Interleukin-10 - metabolism</subject><subject>Interleukin-1beta - metabolism</subject><subject>Receptors, GABA-A - metabolism</subject><subject>Receptors, Immunologic - metabolism</subject><subject>Receptors, Interleukin-10 - metabolism</subject><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqFj02KwkAUhBtBjKhXkHeBQOwkYpZRdGb27qXtvMSnyUvon0Uu4WE8yJxpDIw7wYKiNlUf1EhMZZSkoYylDMTC2mv0VCqzZJVNRBCv5SaL02Qq7l_5NoccDGrsXGug9KwdtQxkAfmiWGMB5x5-2KGp0d-Iw1UExHDxjWLAjuphWSGThkpxVVM7uFEWFBdA7gkqS9RuQOrWDyCl3Rvs72MuxqWqLS7-cyaWh_1x9x12_txgceoMNcr0p9eB-GPhDwIBU_s</recordid><startdate>20221026</startdate><enddate>20221026</enddate><creator>Ruffolo, Gabriele</creator><creator>Alfano, Veronica</creator><creator>Romagnolo, Alessia</creator><creator>Zimmer, Till</creator><creator>Mills, James D</creator><creator>Cifelli, Pierangelo</creator><creator>Gaeta, Alessandro</creator><creator>Morano, Alessandra</creator><creator>Anink, Jasper</creator><creator>Mühlebner, Angelika</creator><creator>Vezzani, Annamaria</creator><creator>Aronica, Eleonora</creator><creator>Palma, Eleonora</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20221026</creationdate><title>GABA A receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β</title><author>Ruffolo, Gabriele ; Alfano, Veronica ; Romagnolo, Alessia ; Zimmer, Till ; Mills, James D ; Cifelli, Pierangelo ; Gaeta, Alessandro ; Morano, Alessandra ; Anink, Jasper ; Mühlebner, Angelika ; Vezzani, Annamaria ; Aronica, Eleonora ; Palma, Eleonora</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_362893543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adult</topic><topic>Child</topic><topic>Drug Resistant Epilepsy</topic><topic>gamma-Aminobutyric Acid</topic><topic>Ganglioglioma - complications</topic><topic>Humans</topic><topic>Interleukin-10 - metabolism</topic><topic>Interleukin-1beta - metabolism</topic><topic>Receptors, GABA-A - metabolism</topic><topic>Receptors, Immunologic - metabolism</topic><topic>Receptors, Interleukin-10 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ruffolo, Gabriele</creatorcontrib><creatorcontrib>Alfano, Veronica</creatorcontrib><creatorcontrib>Romagnolo, Alessia</creatorcontrib><creatorcontrib>Zimmer, Till</creatorcontrib><creatorcontrib>Mills, James D</creatorcontrib><creatorcontrib>Cifelli, Pierangelo</creatorcontrib><creatorcontrib>Gaeta, Alessandro</creatorcontrib><creatorcontrib>Morano, Alessandra</creatorcontrib><creatorcontrib>Anink, Jasper</creatorcontrib><creatorcontrib>Mühlebner, Angelika</creatorcontrib><creatorcontrib>Vezzani, Annamaria</creatorcontrib><creatorcontrib>Aronica, Eleonora</creatorcontrib><creatorcontrib>Palma, Eleonora</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ruffolo, Gabriele</au><au>Alfano, Veronica</au><au>Romagnolo, Alessia</au><au>Zimmer, Till</au><au>Mills, James D</au><au>Cifelli, Pierangelo</au><au>Gaeta, Alessandro</au><au>Morano, Alessandra</au><au>Anink, Jasper</au><au>Mühlebner, Angelika</au><au>Vezzani, Annamaria</au><au>Aronica, Eleonora</au><au>Palma, Eleonora</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GABA A receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β</atitle><jtitle>Scientific reports</jtitle><addtitle>Sci Rep</addtitle><date>2022-10-26</date><risdate>2022</risdate><volume>12</volume><issue>1</issue><spage>17956</spage><pages>17956-</pages><eissn>2045-2322</eissn><abstract>Gangliogliomas (GGs) are low-grade brain tumours that cause intractable focal epilepsy in children and adults. In GG, as in epileptogenic focal malformations (i.e., tuberous sclerosis complex, TSC), there is evidence of sustained neuroinflammation with involvement of the pro-inflammatory cytokine IL-1β. On the other hand, anti-inflammatory mediators are less studied but bear relevance for understanding seizure mechanisms. Therefore, we investigated the effect of the key anti-inflammatory cytokine IL-10 on GABAergic neurotransmission in GG. We assessed the IL-10 dependent signaling by transcriptomic analysis, immunohistochemistry and performed voltage-clamp recordings on Xenopus oocytes microtransplanted with cell membranes from brain specimens, to overcome the limited availability of acute GG slices. We report that IL-10-related mRNAs were up-regulated in GG and slightly in TSC. Moreover, we found IL-10 receptors are expressed by neurons and astroglia. Furthermore, GABA currents were potentiated significantly by IL-10 in GG. This effect was time and dose-dependent and inhibited by blockade of IL-10 signaling. Notably, in the same tissue, IL-1β reduced GABA current amplitude and prevented the IL-10 effect. These results suggest that in epileptogenic tissue, pro-inflammatory mechanisms of hyperexcitability prevail over key anti-inflammatory pathways enhancing GABAergic inhibition. Hence, boosting the effects of specific anti-inflammatory molecules could resolve inflammation and reduce intractable seizures.</abstract><cop>England</cop><pmid>36289354</pmid></addata></record> |
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subjects | Adult Child Drug Resistant Epilepsy gamma-Aminobutyric Acid Ganglioglioma - complications Humans Interleukin-10 - metabolism Interleukin-1beta - metabolism Receptors, GABA-A - metabolism Receptors, Immunologic - metabolism Receptors, Interleukin-10 - metabolism |
title | GABA A receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β |
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