The bone marrow has recently been implicated as a critical responder following stroke. As the site of hematopoiesis, it produces leukocytes that i) can enhance tissue injury or healing in the brain lesion and ii) sustain inflammation in atherosclerotic plaque triggering recurrent stroke. At the same time, leukocytes protect against infection. Clinical stroke data show increased circulating monocyte and neutrophil levels, indicating activation of innate immunity. Stroke patients are at higher risk for recurrent ischemic events (e.g., recurrent stroke) within months of the initial event, potentially due to stroke-associated acceleration of vessel wall inflammation and atherogenesis. A high incidence of post-stroke pneumonia is accompanied by decreased lymphocyte counts, indicating suppression of adaptive immunity. Our preliminary data show that the increased supply of innate immune cells after stroke enhances atherosclerosis in mice with hyperlipidemia (Nature 2012). The mechanism is currently unclear;however, new data obtained for this revised application show a vigorous increase of leukocyte production in the bone marrow after stroke. We thus propose testing the overarching hypothesis that there is important crosstalk between the ischemic brain and the hematopoietic system during the evolution of injury and repair. We hypothesize that ischemic brain injury activates hematopoietic stem cells (HSC) in the bone marrow and introduces a hematopoietic bias towards the myeloid cell lineage. Increased progenitor proliferation, we hypothesize, will lead to neutrophilia and monocytosis. Based on preliminary data and evidence in the literature, we hypothesize that these cells modulate the inflammatory response within the ischemic brain lesion and increase inflammation in atherosclerotic plaques. We propose to study the impact of ischemic stroke on the hematopoietic system in mice. We will follow proliferation, traffic and differentiation of HSC at different time points after stroke. We will investigate how the bone marrow niche, the microenvironment regulating HSC activity, changes after stroke. We will further investigate long-range signals between the brain and the bone marrow that instigate the observed changes. We will study 2 concrete pathways: a) increased sympathetic nervous signaling, which acts through ?3-adrenoreceptors on niche cells to liberate HSC from the bone marrow, and b) HMGB1 released from damaged brain tissue, because this alarmin may act directly on HSC as a toll like receptor ligand to increase proliferation. In serial imaging trials, we will test the hypothesis tht inhibiting sympathetic nervous and HMGB1 signaling decreases post-stroke inflammation in the brain and in atherosclerotic plaque. By so doing, we hope to understand how stroke modulates and mobilizes bone marrow hematopoietic cells, and the contribution of these processes to peripheral tissue inflammation, lesion maturation, atherogenesis, and the risk of stroke recurrence. The proposed research bridges an important intellectual gap between the fields of neuroscience, immunology and hematopoietic stem cell biology by investigating the neuro-immunological interface after stroke, and brings together two groups with complimentary expertise (Nahrendorf, Moskowitz).

Public Health Relevance

The proposed interdisciplinary research program will explore how stroke modulates and mobilizes leukocytes and bone marrow hematopoietic cells, and the contribution of these processes to peripheral tissue inflammation, lesion maturation, atherogenesis, and the risk of stroke recurrence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS084863-01A1
Application #
8754405
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2014-06-15
Project End
2019-04-30
Budget Start
2014-06-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$630,699
Indirect Cost
$266,980
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Courties, Gabriel; Herisson, Fanny; Sager, Hendrik B et al. (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 116:407-17
Swirski, Filip K; Nahrendorf, Matthias (2014) Do vascular smooth muscle cells differentiate to macrophages in atherosclerotic lesions? Circ Res 115:605-6