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Innate immune anti-inflammatory response in human spontaneous intracerebral haemorrhage

Innate immune anti-inflammatory response in human spontaneous intracerebral haemorrhage
Innate immune anti-inflammatory response in human spontaneous intracerebral haemorrhage
Background and Purpose-Spontaneous intracerebral haemorrhage (sICH) is a common form of haemorrhagic 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 spontaneous intracerebral haemorrhage (sICH). Methods- We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, CD206) in brain tissue biospecimens 1-12 days post sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (C-reactive protein, total white cell and monocyte count) over 1-12 days following sICH. Results- In 27 supra-tentorial sICH cases (n=27, median, [IQR] age: 59, [52-80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Antiinflammatory markers (CD163, CD206) were elevated alongside pro-inflammatory markers (CD68, TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7-12 days, p<0.001). CD206 increased at 3-5 days (5.2-fold, p<0.001) then returned to control levels at 7-12 days. The parenchymal immune response combined brain-derived microglia (TMEM119-positive) and invading monocyte-derived macrophages (CD206-positive). In a prospective sICH patient cohort (n=26, age 74, [66-79], NIHSS on admission: 8, [4-17]; 14F/12M) blood CRP concentration and monocyte density (but not WBC) increased postsICH. CRP increased from 0-2 to 3-5 days (8.3-fold, p=0.020) then declined at 7-12 days. Monocytes increased from 0-2 to 3-5 days (1.8-fold, p<0.001) then declined at 7-12 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 post-sICH) for delivery of therapeutics via invading monocytes.
0039-2499
Shatya, Anan
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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
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 haemorrhage. Stroke, [STROKE/2021/034673DR1]. (In Press)

Record type: Article

Abstract

Background and Purpose-Spontaneous intracerebral haemorrhage (sICH) is a common form of haemorrhagic 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 spontaneous intracerebral haemorrhage (sICH). Methods- We performed quantitative analysis of immunohistochemical markers for microglia and macrophages (Iba1, CD68, TMEM119, CD163, CD206) in brain tissue biospecimens 1-12 days post sICH and matched control cases. In a parallel, prospective group of patients, we assayed circulating inflammatory markers (C-reactive protein, total white cell and monocyte count) over 1-12 days following sICH. Results- In 27 supra-tentorial sICH cases (n=27, median, [IQR] age: 59, [52-80.5], 14F/13M) all microglia-macrophage markers increased post-sICH, relative to control brains. Antiinflammatory markers (CD163, CD206) were elevated alongside pro-inflammatory markers (CD68, TMEM119). CD163 increased progressively post-sICH (15.0-fold increase at 7-12 days, p<0.001). CD206 increased at 3-5 days (5.2-fold, p<0.001) then returned to control levels at 7-12 days. The parenchymal immune response combined brain-derived microglia (TMEM119-positive) and invading monocyte-derived macrophages (CD206-positive). In a prospective sICH patient cohort (n=26, age 74, [66-79], NIHSS on admission: 8, [4-17]; 14F/12M) blood CRP concentration and monocyte density (but not WBC) increased postsICH. CRP increased from 0-2 to 3-5 days (8.3-fold, p=0.020) then declined at 7-12 days. Monocytes increased from 0-2 to 3-5 days (1.8-fold, p<0.001) then declined at 7-12 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 post-sICH) for delivery of therapeutics via invading monocytes.

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Accepted/In Press date: 19 May 2021

Identifiers

Local EPrints ID: 449337
URI: http://eprints.soton.ac.uk/id/eprint/449337
ISSN: 0039-2499
PURE UUID: f91ab3ab-d59c-4c83-a699-dda958b5ca5b
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

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Date deposited: 25 May 2021 16:32
Last modified: 26 May 2021 01:37

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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: James Nicoll ORCID iD
Author: Delphine Boche ORCID iD
Author: Atticus Hainsworth

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