Abstract
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.
Highlights
IL-33 is a member of the interleukin-1 (IL-1) cytokine family that plays important roles in various disorders including allergy, autoimmune, or cardiovascular diseases through its receptor ST2 and co-receptor IL-1 accessory protein (IL-1RAcP) [1]
We previously reported the essential role of the IL-33 receptor ST2 in the pathogenesis of experimental cerebral malaria (ECM) caused by Plasmodium berghei Anka (PbA)-infection in mice
We previously showed a deleterious effect of central nervous system (CNS) endogenous IL-33 through the activation of microglia leading to IL-1β release in ECM [10]
Summary
IL-33 is a member of the interleukin-1 (IL-1) cytokine family that plays important roles in various disorders including allergy, autoimmune, or cardiovascular diseases through its receptor ST2 and co-receptor IL-1 accessory protein (IL-1RAcP) [1]. The intraperitoneal administration of antiIL-33 neutralizing antibodies delayed the onset and the severity of EAE [6] These apparently opposite findings highlight the dual function of IL-33. More recently, Saresella et al [8] demonstrated a decrease of IL-33 in the serum of AD patients as compared with healthy controls These clinical data highlight a complex pro- and antiinflammatory properties of IL-33 in AD patients acting both at the central and systemic level. We showed that ST2deficient mice were resistant to PbA-induced neuropathology [9] and demonstrated a deleterious role of CNS endogenous IL-33 in the neuropathogenesis associated with cognitive disorders [10]. 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. The role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
