Evolution of neuropathologic abnormalities associated with blood-brain barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes.
As both astrocytes and cytokines modulate the permeability of cerebral endothelial cells, transgenic animal models which overexpress cytokines, such as interleukin-6 (IL-6), may provide insight into the neuropathological consequences of increased BBB permeability. In this study, a GFAP-IL6 transgenic mouse model and horseradish peroxidase (HRP) were used to investigate BBB permeability and associated neuropathologic changes. In the cerebellum of control mice, the BBB developed between postnatal days 7 and 14. In transgenic mice, the BBB never developed and extensive breakdown was evident in both high- and low-expressor animals by 1 month after birth. Vascular proliferation was apparent from birth in association with development and retention of normal cerebellar architecture until 3 and 6 months in high- and low-expressor animals, respectively. At these times, a leptomeningeal inflammatory infiltrate, vacuolated astrocytic foot processes and endothelial abnormalities were apparent in the cerebellum. At 6 months in high-expressor and 12 months in low-expressor animals, parenchymal inflammation, gliosis, spongiform change, axonal degeneration and macrophage accumulation were evident. The findings suggest that increased production of IL-6 can influence the development and physiologic function of the BBB as well as contribute to parenchymal central nervous system injury.
Brett
F M
FM
Veteran Administration Medical Center, San Diego, California, USA.
Mizisin
A P
AP
Powell
H C
HC
Campbell
I L
IL
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001812:Blood-Brain Barrier; D002531:Cerebellum / Q000648:ultrastructure; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000648:ultrastructure; D015850:Interleukin-6 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability
D015850:Interleukin-6