Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNFα.

Abstract

Event Abstract Back to Event Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNFα. Edel Hennessy1, 2, Eadaoin Griffin1, 2 and Colm Cunningham1, 2 1 Trinity College Dublin, School of Biochemistry and Immunology, Ireland 2 Trinity College Dublin, Trinity College Institute of Neuroscience, Ireland Microgliosis and astrogliosis are standard pathological features of neurodegenerative disease. Microglia are primed by chronic neurodegeneration such that toll-like receptor agonists, such as lipopolysaccharide (LPS), drive exaggerated cytokine responses on this background. However, sterile inflammatory insults are more common than direct CNS infection in the degenerating brain and these insults drive robust IL-1β and TNF-α responses. It is unclear whether these pro-inflammatory cytokines can directly induce exaggerated responses in the degenerating brain. We hypothesised that glial cells in the hippocampus of animals with chronic neurodegenerative disease (ME7 prion disease) would display exaggerated responses to central cytokine challenges. TNF-α or IL-1β were administered intrahippocampally to ME7-inoculated mice and normal brain homogenate-injected (NBH) controls. Both IL-1β and TNF-α produced robust IL-1β synthesis in ME7 microglia but this was very limited in NBH animals. In addition there was strong nuclear localisation of the NFkB subunit p65 in the astrocyte population, associated with marked astrocytic synthesis of the chemokines CXCL1 and CCL2 in response to both cytokine challenges in ME7 animals. Conversely, very limited expression of these chemokines was apparent in NBH animals similarly challenged. Thus, astrocytes are primed in the degenerating brain to produce exaggerated chemokine responses to acute stimulation with pro-inflammatory cytokines. Furthermore, this results in markedly increased neutrophils, macrophage/microglia and T cells in the diseased brain and increased CNS cellular proliferation. These data have significant implications for acute sterile inflammatory insults such as stroke and traumatic brain injury occurring on a background of aging or neurodegeneration. Acknowledgements This work was supported by The Wellcome Trust and EH was supported by a Trinity College Dublin Research Studentship. We also wish to acknowledge the gift of the MBS-1 neutrophil antibody from Professor Daniel Anthony, Oxford, UK and Gavin MacManus for technical assistance with confocal microscopy. Keywords: Neuroinflammation, astrocyte, Microglia, cytokine, chemokine, IL-1β, TNF-α, CCL2, MCP-1, CXCL1, CINC-1, GROα, kc, proliferation, Infiltration, Neutrophil, macrophage, neurodegeneration, priming, sensitization Conference: Neuroscience Ireland Young Neuroscientists Symposium 2014 , Dublin, Ireland, 20 Sep - 20 Sep, 2014. Presentation Type: Oral Presentation Topic: Early Career Neuroscience Citation: Hennessy E, Griffin E and Cunningham C (2014). Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNFα.. Front. Neurosci. Conference Abstract: Neuroscience Ireland Young Neuroscientists Symposium 2014 . doi: 10.3389/conf.fnins.2014.87.00011 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 08 Sep 2014; Published Online: 08 Sep 2014. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Edel Hennessy Eadaoin Griffin Colm Cunningham Google Edel Hennessy Eadaoin Griffin Colm Cunningham Google Scholar Edel Hennessy Eadaoin Griffin Colm Cunningham PubMed Edel Hennessy Eadaoin Griffin Colm Cunningham Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.