Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments
Open Access
- 11 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Neuroinflammation
- Vol. 17 (1), 1-15
- https://doi.org/10.1186/s12974-020-01939-6
Abstract
Background Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms. Methods We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1 alpha beta deficient mice. Chronic minocycline administration was performed and cognitive functions were examined trough spatial habituation test. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and fluorescence-activated cell sorting (FACS). Results We showed that IL-33 administration in mice led to a spatial memory performance defect associated with an increase of inflammatory markers in the hippocampus while minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ demonstrated an increase of proximal intersections per radius in each part of the hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting analysis on isolated microglia, revealed overexpression of IL-1 beta, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1 alpha beta deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection. Conclusion Thus, hippocampal IL-33 induced an inflammatory state, including IL-1 beta overexpression by microglia cells, being causative of the cognitive impairment. These results highlight the pathological role for IL-33 in the central nervous system, independently of a specific neuropathological model.Keywords
Funding Information
- French Ministry of Research
- European funding in the Region Centre-Val de Loire (2016-00110366)
- Key Laboratory of Highway Construction and Maintenance Technology in the Loess Region of Shanxi Transportation Research Institute (2016-EX005756)
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