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-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). 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-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. 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.

Breast cancer in schizophrenia could be interleukin-33-mediated

“…Carlock et al [ 51 ] in 2017 pointed out that deficiency of IL-33 caused tau abnormality and late-onset neurodegeneration in the cerebral cortex and hippocampus, accompanied by memory impairment. A recent study suggested that IL-33 gene mutations affect susceptibility to late-onset AD, which in turn confirms that IL-33 may exacerbate neuroinflammation and cognitive decline[ 52 , 53 ].…”

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

“…In the newborn brain with Zika virusinduced microcephaly, IL-33 is significantly upregulated compared to that in newborn brains with microcephaly without virus infection (78,79). IL-33 has been found to positively correlate with IL-1b expression (79,80), implying that IL-33 might play a role in the proinflammatory response in virus infection. In addition, an in vitro study demonstrated that HIV infection induces IL-33 release from neurons and ST2 upregulation in astrocytes.…”

Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale

“…A representative example is provided by IL-33, a member of the IL-1 family that showed either neuroprotective or neurodegenerative effects in different experimental conditions. Intraperitoneal injections (50 mg/kg, about 1.15 mg per animal, 10 days) followed by intrahippocampal injection (400 ng by side) of IL-33 in 8-week-old mice, evoked neuroinflammation and cognitive impairment [ 170 ], whereas intraperitoneal injections (200 ng, 7 days) of IL-33 in transgenic mouse models of AD (mice, 48 weeks old) mobilized microglia to prevent and clear Aβ-deposits, thus ameliorating cognitive impairment [ 171 ]. Of note, IL-33 released by astrocytes has been suggested to modulate typical microglia activities such as the pruning of synapses in mouse embryos during maturation [ 50 ] and modulation of synaptic plasticity in adult mice (16 weeks old) [ 104 ].…”