Role of interleukin-1 in prion disease-associated astrocyte activation.
Prion-induced chronic neurodegeneration has a substantial inflammatory component, and the activation of glia cells may play an important role in disease development and progression. However, the functional contribution of cytokines to the development of the gliosis in vivo was never systematically studied. We report here that the expression of interleukin-1beta (IL-1beta), IL-1beta-converting enzyme, and IL-1 receptor type 1 (IL-1RI) is up-regulated in a murine scrapie model. The scrapie-induced gliosis in IL-1RI(-/-) mice was characterized by an attenuated activation of astrocytes in the asymptomatic stage of the disease and a reduced expression of CXCR3 ligands. Furthermore, the accumulation of the misfolded isoform of the prion protein PrP(Sc) was significantly delayed in the IL-1RI(-/-) mice. These observations indicate that IL-1 is a driver of the scrapie-associated astrocytosis and possibly the accompanying amyloid deposition. In addition, scrapie-infected IL-1RI-deficient (IL-1RI(-/-)) mice showed a delayed disease onset and significantly prolonged survival times suggesting that an anti-inflammatory therapeutical approach to suppress astrocyte activation and/or glial IL-1 expression may help to delay disease onset in established prion infections of the central nervous system.
Project "Neurodegenerative Diseases," Robert-Koch-Institute, Nordufer 20, 13353 Berlin, Germany.
Julia
J
Schultz
Anja
A
Schwarz
Sabine
S
Neidhold
Michael
M
Burwinkel
Constanze
C
Riemer
Dietrich
D
Simon
Manfred
M
Kopf
Markus
M
Otto
Michael
M
Baier
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D020170:Caspase 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D005911:Gliosis / Q000209:etiology*; D007375:Interleukin-1 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D015996:Survival Rate; D015854:Up-Regulation
C515188:Cxcr3 protein, mouse; D007375:Interleukin-1; D008024:Ligands; D018620:PrPSc Proteins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D020170:Caspase 1