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

The authors are grateful for funding provided by the Medical Research Council (NJR MRC Research Professorship), the European Union’s Seventh Framework Programme (FP7/2008-2013) under grant agreements no. 201024 and no. 202213 (European Stroke Network, NJR, AD), and the Wellcome Trust (NH, RG).

Adam Denes1, Barry W McColl2, Sophie F Leow-Dyke1, Katie Z Chapman1,3, Neil E Humphreys1, Richard K Grencis1, Stuart M Allan1 and Nancy J Rothwell1

  1. 1Faculty of Life Sciences, University of Manchester, Manchester, UK
  2. 2Neuropathogenesis Division, The Roslin Institute and R(D)SVS, University of Edinburgh, Roslin, UK

Correspondence: Dr A Denes, Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK. E-mail: adam.denes@manchester.ac.uk

3Current address: Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.

Received 26 July 2010; Revised 22 September 2010; Accepted 11 October 2010; Published online 3 November 2010.

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Abstract

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.

Keywords:

acute-phase response; autonomic; bone marrow; cytokine; granulocyte; stroke

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