Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNFα.
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1
Trinity College Dublin, School of Biochemistry and Immunology, Ireland
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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
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Received:
08 Sep 2014;
Published Online:
08 Sep 2014.