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

Wong, Raymond and Lénárt, Nikolett and Hill, Laura and Toms, Lauren and Coutts, Graham and Martinecz, Bernadett and Császár, Eszter and Nyíri, Gábor and Dénes, Ádám (2019) Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. BRAIN BEHAVIOR AND IMMUNITY, 76. pp. 126-138. ISSN 0889-1591

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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.

Item Type: Article
Additional Information: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23538, Germany Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom Cited By :2 Export Date: 29 November 2019 CODEN: BBIME Correspondence Address: Denés, A.; “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Hungary; email: denesa@koki.hu Chemicals/CAS: nestin, 146315-66-4; tamoxifen, 10540-29-1 Funding details: Office of Research, Innovation and Economic Development, California State Polytechnic University, Pomona, NN 125643 Funding details: British Heart Foundation, PG/13/8/29989 Funding details: ERC-CoG 724994 Funding details: Medical Research Council, G0801296 Funding details: MUGEN LSHG‐CT‐2005‐005203 Funding details: 2017-1.2.1-NKP-2017-00002 Funding text 1: 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. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23538, Germany Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom Cited By :3 Export Date: 30 March 2020 CODEN: BBIME Correspondence Address: Denés, A.; “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Hungary; email: denesa@koki.hu Chemicals/CAS: nestin, 146315-66-4; tamoxifen, 10540-29-1; Cytokines; Interleukin-1; Receptors, Interleukin-1; Receptors, Interleukin-1 Type I Funding details: British Heart Foundation, BHF, PG/13/8/29989 Funding details: MUGEN LSHG‐CT‐2005‐005203 Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Medical Research Council, MRC, G0801296 Funding details: NN 125643 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: 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. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23538, Germany Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom Cited By :3 Export Date: 15 April 2020 CODEN: BBIME Correspondence Address: Denés, A.; “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Hungary; email: denesa@koki.hu Chemicals/CAS: nestin, 146315-66-4; tamoxifen, 10540-29-1; Cytokines; Interleukin-1; Receptors, Interleukin-1; Receptors, Interleukin-1 Type I Funding details: British Heart Foundation, BHF, PG/13/8/29989 Funding details: MUGEN LSHG‐CT‐2005‐005203 Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Medical Research Council, MRC, G0801296 Funding details: NN 125643 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: 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. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23538, Germany Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom Cited By :3 Export Date: 22 April 2020 CODEN: BBIME Correspondence Address: Denés, A.; “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Hungary; email: denesa@koki.hu Chemicals/CAS: nestin, 146315-66-4; tamoxifen, 10540-29-1; Cytokines; Interleukin-1; Receptors, Interleukin-1; Receptors, Interleukin-1 Type I Funding details: British Heart Foundation, BHF, PG/13/8/29989 Funding details: MUGEN LSHG‐CT‐2005‐005203 Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Medical Research Council, MRC, G0801296 Funding details: NN 125643 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: 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. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23538, Germany Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom Cited By :3 Export Date: 29 May 2020 CODEN: BBIME Correspondence Address: Denés, A.; “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Hungary; email: denesa@koki.hu Chemicals/CAS: nestin, 146315-66-4; tamoxifen, 10540-29-1; Cytokines; Interleukin-1; Receptors, Interleukin-1; Receptors, Interleukin-1 Type I Funding details: British Heart Foundation, BHF, PG/13/8/29989 Funding details: MUGEN LSHG‐CT‐2005‐005203 Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Medical Research Council, MRC, G0801296 Funding details: NN 125643 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: 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. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, United Kingdom “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Szigony u. 43, Budapest, 1083, Hungary Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, 23538, Germany Department of Infection, Immunity & Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S10 2RX, United Kingdom Cited By :8 Export Date: 21 September 2020 CODEN: BBIME Correspondence Address: Denés, A.; “Momentum” Laboratory of Neuroimmunology, Institute of Experimental Medicine, Szigony u. 43, Hungary; email: denesa@koki.hu Chemicals/CAS: nestin, 146315-66-4; tamoxifen, 10540-29-1; Cytokines; Interleukin-1; Receptors, Interleukin-1; Receptors, Interleukin-1 Type I Funding details: British Heart Foundation, BHF, PG/13/8/29989 Funding details: MUGEN LSHG‐CT‐2005‐005203 Funding details: Magyar Tudományos Akadémia, MTA, ERC-CoG 724994 Funding details: Medical Research Council, MRC, G0801296 Funding details: NN 125643 Funding details: KTIA_13_NAP-A-I/2 Funding text 1: 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.
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 23 Sep 2020 08:15
Last Modified: 23 Sep 2020 08:15
URI: http://real.mtak.hu/id/eprint/114125

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