Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation

Background: Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in P...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Tarek Shaker, Bidisha Chattopadhyaya, Bénédicte Amilhon, Graziella Di Cristo, Alexander G. Weil
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Caspase-1 hippocampus Hyperexcitability Inflammasome Organotypic cultures Peripheral blood mononuclear cells Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/4bdea1475d054ca59f21452b9df59894
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4bdea1475d054ca59f21452b9df59894
record_format	dspace
spelling	oai:doaj.org-article:4bdea1475d054ca59f21452b9df598942021-11-12T04:26:30ZTransduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation1095-953X10.1016/j.nbd.2021.105535https://doaj.org/article/4bdea1475d054ca59f21452b9df598942021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002849https://doaj.org/toc/1095-953XBackground: Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking infiltration of activated PBMCs into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS. Methods: To establish our model, we first extracted PBMCs from rat spleen, then, immunologically primed PBMCs with lipopolysaccharide (LPS), followed by further activation with nigericin. Thereafter, we co-cultured these activated PBMCs with organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. We further targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 h, we analyzed inflammation markers in the cortex and the hippocampus using semiquantitative immunofluorescence. In addition, we analyzed neuronal activity by whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons. Results: In the cortex, co-culturing immunoreactive PBMCs treated with LPS + nigericin on top of OCHSCs upregulated inflammatory markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs (i.e. treated with LPS only), to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, prevented neuroinflammation and hippocampal hyperexcitability in OCHSCs. Conclusions: Our study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity.Tarek ShakerBidisha ChattopadhyayaBénédicte AmilhonGraziella Di CristoAlexander G. WeilElsevierarticleCaspase-1hippocampusHyperexcitabilityInflammasomeOrganotypic culturesPeripheral blood mononuclear cellsNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 160, Iss , Pp 105535- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Caspase-1 hippocampus Hyperexcitability Inflammasome Organotypic cultures Peripheral blood mononuclear cells Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Caspase-1 hippocampus Hyperexcitability Inflammasome Organotypic cultures Peripheral blood mononuclear cells Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Tarek Shaker Bidisha Chattopadhyaya Bénédicte Amilhon Graziella Di Cristo Alexander G. Weil Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation
description	Background: Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking infiltration of activated PBMCs into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS. Methods: To establish our model, we first extracted PBMCs from rat spleen, then, immunologically primed PBMCs with lipopolysaccharide (LPS), followed by further activation with nigericin. Thereafter, we co-cultured these activated PBMCs with organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. We further targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 h, we analyzed inflammation markers in the cortex and the hippocampus using semiquantitative immunofluorescence. In addition, we analyzed neuronal activity by whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons. Results: In the cortex, co-culturing immunoreactive PBMCs treated with LPS + nigericin on top of OCHSCs upregulated inflammatory markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs (i.e. treated with LPS only), to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, prevented neuroinflammation and hippocampal hyperexcitability in OCHSCs. Conclusions: Our study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity.
format	article
author	Tarek Shaker Bidisha Chattopadhyaya Bénédicte Amilhon Graziella Di Cristo Alexander G. Weil
author_facet	Tarek Shaker Bidisha Chattopadhyaya Bénédicte Amilhon Graziella Di Cristo Alexander G. Weil
author_sort	Tarek Shaker
title	Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation
title_short	Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation
title_full	Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation
title_fullStr	Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation
title_full_unstemmed	Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation
title_sort	transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by caspase-1 activation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/4bdea1475d054ca59f21452b9df59894
work_keys_str_mv	AT tarekshaker transductionofinflammationfromperipheralimmunecellstothehippocampusinducesneuronalhyperexcitabilitymediatedbycaspase1activation AT bidishachattopadhyaya transductionofinflammationfromperipheralimmunecellstothehippocampusinducesneuronalhyperexcitabilitymediatedbycaspase1activation AT benedicteamilhon transductionofinflammationfromperipheralimmunecellstothehippocampusinducesneuronalhyperexcitabilitymediatedbycaspase1activation AT grazielladicristo transductionofinflammationfromperipheralimmunecellstothehippocampusinducesneuronalhyperexcitabilitymediatedbycaspase1activation AT alexandergweil transductionofinflammationfromperipheralimmunecellstothehippocampusinducesneuronalhyperexcitabilitymediatedbycaspase1activation
_version_	1718431288287821824

Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation

Ejemplares similares