Innate immune anti-inflammatory response in human spontaneous intracerebral hemorrhage
Innate immune anti-inflammatory response in human spontaneous intracerebral hemorrhage
BACKGROUND AND PURPOSE: Spontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH. METHODS: We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH. RESULTS: In 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52-80.5], 14F/13M) all microgliamacrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7-12 days, P<0.001). CD206 increased at 3 to 5 days (5.2-fold, P<0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocytederived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66-79], National Institutes of Health Stroke Scale on admission: 8 [4-17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P=0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P<0.001) then declined at 7 to 12 days. CONCLUSIONS: An anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3-5 days postsICH) for delivery of therapeutics via invading monocytes.
Immunity, Inflammation, Macrophages, Microglia, Monocytes
3613-3623
Shatya, Anan
633f6784-c8aa-4590-a7ed-60e77a81acce
Bridges, Leslie
4e024fe8-66d3-45c8-a4e7-fc372be7e5c7
Williams, Rebecca
c8d08cdd-67bb-4322-acf4-055a81de875c
Trippier, Sarah
b4ee1042-a725-49b9-aba0-6c56aeffed8d
Zhang, Liqun
f0dda2e0-4050-4756-85e7-7a8949fd8115
Pereira, Anthony C.
6c0744c9-f280-44a8-b480-53908ff563be
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Hainsworth, Atticus
82138667-8a34-4d2d-8da2-c55b292ca59c
20 July 2021
Shatya, Anan
633f6784-c8aa-4590-a7ed-60e77a81acce
Bridges, Leslie
4e024fe8-66d3-45c8-a4e7-fc372be7e5c7
Williams, Rebecca
c8d08cdd-67bb-4322-acf4-055a81de875c
Trippier, Sarah
b4ee1042-a725-49b9-aba0-6c56aeffed8d
Zhang, Liqun
f0dda2e0-4050-4756-85e7-7a8949fd8115
Pereira, Anthony C.
6c0744c9-f280-44a8-b480-53908ff563be
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Hainsworth, Atticus
82138667-8a34-4d2d-8da2-c55b292ca59c
Shatya, Anan, Bridges, Leslie, Williams, Rebecca, Trippier, Sarah, Zhang, Liqun, Pereira, Anthony C., Nicoll, James, Boche, Delphine and Hainsworth, Atticus
(2021)
Innate immune anti-inflammatory response in human spontaneous intracerebral hemorrhage.
Stroke, , [STROKE/2021/034673DR1].
(doi:10.1161/STROKEAHA.121.034673).
Abstract
BACKGROUND AND PURPOSE: Spontaneous intracerebral hemorrhage (sICH) is a common form of hemorrhagic stroke, with high mortality and morbidity. Pathophysiological mechanisms in sICH are poorly understood and treatments limited. Neuroinflammation driven by microglial-macrophage activation contributes to brain damage post-sICH. We aim to test the hypothesis that an anti-inflammatory (repair) process occurs in parallel with neuroinflammation in clinical sICH. METHODS: We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, and CD206) in brain tissue biospecimens 1 to 12 days post-sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (CRP [C-reactive protein], total white cell, and monocyte count) over 1 to 12 days following sICH. RESULTS: In 27 supratentorial sICH cases (n=27, median [interquartile range] age: 59 [52-80.5], 14F/13M) all microgliamacrophage markers increased post-sICH, relative to control brains. Anti-inflammatory markers (CD163 and CD206) were elevated alongside proinflammatory markers (CD68 and TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7-12 days, P<0.001). CD206 increased at 3 to 5 days (5.2-fold, P<0.001) then returned to control levels at 7 to 12 days. The parenchymal immune response combined brain-derived microglia (TMEM119 positive) and invading monocytederived macrophages (CD206 positive). In a prospective sICH patient cohort (n=26, age 74 [66-79], National Institutes of Health Stroke Scale on admission: 8 [4-17]; 14F/12M) blood CRP concentration and monocyte density (but not white blood cell) increased post-sICH. CRP increased from 0 to 2 to 3 to 5 days (8.3-fold, P=0.020) then declined at 7 to 12 days. Monocytes increased from 0 to 2 to 3 to 5 days (1.8-fold, P<0.001) then declined at 7 to 12 days. CONCLUSIONS: An anti-inflammatory pathway, enlisting native microglia and blood monocytes, occurs alongside neuroinflammation post-sICH. This novel pathway offers therapeutic targets and a window of opportunity (3-5 days postsICH) for delivery of therapeutics via invading monocytes.
Text
ICH Manuscript STROKE
- Accepted Manuscript
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Accepted/In Press date: 19 May 2021
Published date: 20 July 2021
Additional Information:
Funding Information:
We gratefully acknowledge tissue and blood donors and their families, St George’s University Hospitals NHS Foundation Trust Brain Bank; the North Bristol NHS Trust and University Hospitals Plymouth NHS Trust as part of the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research; The Oxford Brain Bank; and UCI Alzheimer’s Disease Research Center (UCI-ADRC), Institute for Memory Impairments and Neurological Disorders, University of California, Irvine. We thank their colleagues in St George’s Healthcare NHS Trust Cellular Pathology Service and St George’s Imaging Resource Facility especially Gregory Perry. We are grateful to Professor Margaret M Esiri FRCPath, University of Oxford, for helpful discussions. We thank Bassam Shtaya, Oasis Academy Byron, Coulsdon, for drawing the graphic abstract.
Funding Information:
This study was funded by the Molecular and Clinical Sciences Research Institute, St George’s, University of London (grant number 10717-19 to Dr Shtaya). Dr Shtaya is the recipient of a Clinical Lectureship from the National Institute for Health and Research (NIHR CL-2015-16-001), United Kingdom. Work in Dr Hainsworth’s laboratory is funded by ADDF and UK Alzheimer’s Society (Project Ref 20140901) and by the UK MRC (MR/R005567/1).
Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
Keywords:
Immunity, Inflammation, Macrophages, Microglia, Monocytes
Identifiers
Local EPrints ID: 449337
URI: http://eprints.soton.ac.uk/id/eprint/449337
ISSN: 0039-2499
PURE UUID: f91ab3ab-d59c-4c83-a699-dda958b5ca5b
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Date deposited: 25 May 2021 16:32
Last modified: 17 Mar 2024 06:35
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Contributors
Author:
Anan Shatya
Author:
Leslie Bridges
Author:
Rebecca Williams
Author:
Sarah Trippier
Author:
Liqun Zhang
Author:
Anthony C. Pereira
Author:
Atticus Hainsworth
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