Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons

Raymond Wong, Nikolett Lénárt, Laura Hill, Lauren Toms, Graham Coutts, Bernadett Martinecz, Eszter Császár, Gábor Nyiri, Athina Papaemmanouil, Ari Waisman, Werner Müller, Markus Schwaninger, Nancy Rothwell, Sheila Francis, Emmanuel Pinteaux, Adam Denés, Stuart M. Allan

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.

Original languageEnglish
Pages (from-to)126-138
Number of pages13
JournalBrain, Behavior, and Immunity
Volume76
DOIs
Publication statusPublished - Feb 2019

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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    Wong, R., Lénárt, N., Hill, L., Toms, L., Coutts, G., Martinecz, B., Császár, E., Nyiri, G., Papaemmanouil, A., Waisman, A., Müller, W., Schwaninger, M., Rothwell, N., Francis, S., Pinteaux, E., Denés, A., & Allan, S. M. (2019). Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. Brain, Behavior, and Immunity, 76, 126-138. https://doi.org/10.1016/j.bbi.2018.11.012