Innate Immune Anti-Inflammatory Response in Human Spontaneous Intracerebral Hemorrhage

Author:

Shtaya Anan12ORCID,Bridges Leslie R.13,Williams Rebecca4ORCID,Trippier Sarah4,Zhang Liqun4ORCID,Pereira Anthony C.14,Nicoll James A.R.5,Boche Delphine5ORCID,Hainsworth Atticus H.14ORCID

Affiliation:

1. Molecular and Clinical Sciences Research Institute, St George’s University of London, United Kingdom (A.S., L.R.B., A.C.P., A.H.H.).

2. Wessex Spinal Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (A.S.).

3. Department of Cellular Pathology (L.R.B.), St George’s University Hospitals NHS Foundation Trust, London, United Kingdom.

4. Neurology Department (R.W., S.T., L.Z., A.C.P., A.H.H.), St George’s University Hospitals NHS Foundation Trust, London, United Kingdom.

5. Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom (J.A.R.N., D.B.).

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 microglia-macrophage 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 monocyte-derived 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 post-sICH) for delivery of therapeutics via invading monocytes.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Advanced and Specialized Nursing,Cardiology and Cardiovascular Medicine,Neurology (clinical)

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