Experimental stroke-induced changes in the bone marrow reveal complex regulation of leukocyte responses

• Published in: Journal of cerebral blood flow and metabolism Vol. 31; no. 4; pp. 1036 - 1050
• Main Authors: Denes, Adam, McColl, Barry W, Leow-Dyke, Sophie F, Chapman, Katie Z, Humphreys, Neil E, Grencis, Richard K, Allan, Stuart M, Rothwell, Nancy J
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.04.2011; Nature Publishing Group; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Bone Marrow - pathology; Bone Marrow Cells - physiology; Cytokines - metabolism; Electrophoresis, Polyacrylamide Gel; Endotoxins - toxicity; Flow Cytometry; Functional Laterality - physiology; Granulocytes - metabolism; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Immunohistochemistry; Infarction, Middle Cerebral Artery - pathology; Inflammation - pathology; Killer Cells, Natural - physiology; Leukocytes - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myeloid Cells - physiology; Nervous system (semeiology, syndromes); Neurology; NF-kappa B - metabolism; Original; Receptors, Interleukin-8B - metabolism; Stroke - pathology; T-Lymphocytes - physiology; Vascular diseases and vascular malformations of the nervous system; cytokine; granulocyte; autonomic; acute-phase response; stroke; bone marrow; Stroke; Nervous system diseases; Leukocyte; Cardiovascular disease; Cerebral disorder; Vascular disease; Central nervous system disease; Bone marrow; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2010.198

Stroke induces a systemic response that involves rapid activation of inflammatory cascades, followed later by immunodepression. Experimental stroke-induced responses in the bone marrow, which is the primary source of circulating monocytes and granulocytes, have not been investigated previously. We show that cerebral ischaemia induced early (4 hours) release of CXCR2-positive granulocytes from the bone marrow, which was associated with rapid systemic upregulation of CXCL1 (a ligand for CXCR2) and granulocyte-colony-stimulating factor, a key cytokine involved in the mobilisation of bone marrow leukocytes. This process involves rapid activation of nuclear factor-κB and p38 mitogen-activated protein kinase in bone marrow myeloid cells. T-cell numbers in the bone marrow increased after stroke, and bone marrow cells did not show suppressed cytokine response to bacterial endotoxin stimulation in vitro. Stroke-induced laterality observed in the brain stem and in the bone marrow indicates direct involvement of the autonomic nervous system in stroke-induced cell mobilisation. We also show that systemic inflammatory changes and leukocyte responses in the bone marrow are profoundly affected by both anaesthetic and surgical stress. We conclude that stroke influences leukocyte responses in the bone marrow through multiple mechanisms and suggest that preclinical studies should take into consideration the effect of surgical manipulation in experimental models of stroke.