TY - JOUR
T1 - Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons
AU - Wong, Raymond
AU - Lénárt, Nikolett
AU - Hill, Laura
AU - Toms, Lauren
AU - Martinecz, Bernadett
AU - Császár, Eszter
AU - Nyiri, Gábor
AU - Papaemmanouil, Athina
AU - Waisman, Ari
AU - Muller, Werner
AU - Schwaninger, Markus
AU - Rothwell, Nancy
AU - Francis, Sheila
AU - Pinteaux, Emmanuel
AU - Denes, Adam
AU - Allan, Stuart
N1 - Funding Information:
This work was supported with funding from the British Heart Foundation (grant ref: PG/13/8/29989 to SA, EP and NJR), the Hungarian Brain Research Program [KTIA_13_NAP-A-I/2 (AD) and 2017-1.2.1-NKP-2017-00002 (GN)], National Research, Development and Innovation Office, NN 125643 (GN), the ‘Momentum’ Program of the Hungarian Academy of Sciences (AD) and ERC-CoG 724994 (AD). The generation of the IL‐1R1 fl/fl mice was funded by FP7/EU Project MUGEN (MUGEN LSHG‐CT‐2005‐005203) to WM and the Medical Research Council (G0801296) to SA, EP and NJR.
Publisher Copyright:
© 2018 The Authors
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/11/16
Y1 - 2018/11/16
N2 - 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.
AB - 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.
U2 - 10.1016/j.bbi.2018.11.012
DO - 10.1016/j.bbi.2018.11.012
M3 - Article
C2 - 30453020
SN - 0889-1591
VL - 76
SP - 126
EP - 138
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
M1 - 0
ER -