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

Brain Behav Immun. 2019 Feb;76:126-138. doi: 10.1016/j.bbi.2018.11.012. Epub 2018 Nov 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Brain Injuries / metabolism
  • Brain Ischemia / immunology*
  • Brain Ischemia / metabolism
  • Cholinergic Neurons / metabolism
  • Cholinergic Neurons / physiology
  • Cytokines / metabolism
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology
  • Inflammation / metabolism
  • Interleukin-1 / metabolism*
  • Interleukin-1 / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Receptors, Interleukin-1 / metabolism
  • Receptors, Interleukin-1 Type I / metabolism
  • Signal Transduction

Substances

  • Cytokines
  • Interleukin-1
  • Receptors, Interleukin-1
  • Receptors, Interleukin-1 Type I