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Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.

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?? 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?, 48?h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1?? 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? 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.

SUBMITTER: Reverchon F

PROVIDER: S-EPMC7488545 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.

Reverchon Flora F de Concini Vidian V Larrigaldie Vanessa V Benmerzoug Sulayman S Briault Sylvain S Togbé Dieudonnée D Ryffel Bernhard B Quesniaux Valérie F J VFJ Menuet Arnaud A

Journal of neuroinflammation 20200911 1

<h4>Background</h4>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.<h4>Methods</h4>We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ deficient mic ...[more]

PMID: 32917228

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Project description:BackgroundAlzheimer's disease (AD) pathogenesis is associated with amyloid-β (Aβ)-induced neuroinflammation. In AD, the activation of microglia caused by Aβ accumulation is followed by the synthesis and release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα), and ultimately leads to cognitive impairments. Clausena harmandiana (CH) is a medicinal plant in the Rutaceae family and has been used in folk medicine to relieve illnesses such as stomachache and headache, and as a health tonic. Interestingly, CH root extract (CHRE) has several anti-inflammatory and other pharmacological activities, but there are no studies in AD-like animal models.ObjectivesThis study aims to evaluate the effects of CHRE on cognitive impairments, increased Aβ1-42 protein levels, and neuroinflammation in Aβ1-42-induced rats.MethodsForty-eight adult male Sprague-Dawley rats (250-300 g) were randomly divided into 6 groups (n = 8) of the sham control, V + Aβ, CB + Aβ CHRE125 + Aβ, CHRE250 + Aβ, and CHRE500 + Aβ. Sodium carboxymethylcellulose, Celebrex (10 mg/kg BW) and CHRE (125, 250, and 500 mg/kg BW) were given orally or without any treatment for 35 days. On day 21, aggregated Aβ1-42 at a concentration of 1 μg/μl were injected into both lateral ventricles (1 μl/side) of all treated rats, while sterilized normal saline were injected to untreated rats. Ten days later, the novel object recognition test was performed to assess their recognition memory. At the end of the test period, an overdose of thiopental sodium (120 mg/kg BW) and transcardial perfusion with 0.9% normal saline solution were used to euthanize all rats. Then Aβ1-42 protein levels and the expression of inflammatory markers (CD11b-positive microglia, IL-1β, and TNFα) were investigated in the cerebral cortex and hippocampus.ResultsPretreatment with CHRE at all doses could attenuate short- and long-term impairments in recognition memory. Additionally, CHRE also inhibited the increase of Aβ1-42 protein levels and the expression of inflammatory markers in both brain regions as well as receiving Celebrex.ConclusionsThis suggests that preventive treatment of CHRE might be a potential therapy against cognitive impairments via reducing Aβ1-42 protein levels and neuroinflammation caused by Aβ1-42.

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Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.

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Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.

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