Hippocampal interleukin-33 mediates neuroinflammation induced cognitive impairments

Background: Interleukin (IL)-33 is expressed in 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 induced a local IL-33 release by intra-hippocampal injection of recombinant mouse IL-33 (rmIL-33) into C57BL/6J (WT) and IL-1ab deficient mice. Chronic minocycline administration was done and cognitive functions were examined trough short- and long-term memory assays. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and Fluorescence-activated cell sorting. Results: We showed that IL-33 administration in mice led to a long-term memory defect associated with an increase of inflammatory markers in hippocampus while, minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ was performed and demonstrated an increase of proximal intersections per radius in each part of hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting performed on isolated microglia, revealed an overexpression of IL-1β, 48h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1ab deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection. Conclusion: Thus, hippocampal IL-33 induced an inflammatory state, including IL-1β 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.