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Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments

  • Reverchon, Flora1, 2
  • de Concini, Vidian1
  • Larrigaldie, Vanessa1
  • Benmerzoug, Sulayman1, 3
  • Briault, Sylvain1, 4
  • Togbé, Dieudonnée5
  • Ryffel, Bernhard1
  • Quesniaux, Valérie F. J.1
  • Menuet, Arnaud1
  • 1 CNRS and University of Orléans, 3B rue de la Ferollerie, Orléans, 45071, France , Orléans (France)
  • 2 Current address: Center for Molecular Biophysics, CNRS UPR4301, Orléans, 45071, France , Orléans (France)
  • 3 CHUV, Lausanne, Switzerland , Lausanne (Switzerland)
  • 4 Regional Hospital, Orléans, France , Orléans (France)
  • 5 Artimmune SAS, 13 Avenue Buffon, Orléans-Cedex 2, 45071, France , Orléans-Cedex 2 (France)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
Sep 11, 2020
DOI: 10.1186/s12974-020-01939-6
Springer Nature


BackgroundInterleukin (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.MethodsWe administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ 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).ResultsWe 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-1β, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1αβ deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection.ConclusionThus, 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.

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