GABAA receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β

• Published in: Scientific reports 2022-10, Vol.12 (1), p.17956-17956, Article 17956
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/378; 631/443; Astrocytes; Brain slice preparation; Brain tumors; Cell membranes; Cytokines; Epilepsy; Humanities and Social Sciences; IL-1β; Immunohistochemistry; Inflammation; Interleukin 10; multidisciplinary; Neurotransmission; Oocytes; Science; Science (multidisciplinary); Seizures; Transcriptomics; Tuberous sclerosis; γ-Aminobutyric acid A receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-22806-9

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.