Gabriel Courties1, Vanessa Frodermann1, Lisa Honold1, Yi Zheng1, Fanny Herisson1, Maximilian J Schloss1, Yuan Sun1, Jessy Presumey2, Nicolas Severe3,4,5, Camilla Engblom1, Maarten Hulsmans1, Sebastian Cremer1, David Rohde1, Mikael J Pittet1, David T Scadden3,4,5, Filip K Swirski1, Dong-Eog Kim6, Michael A Moskowitz7, Matthias Nahrendorf1,8. 1. From the Center for Systems Biology and Radiology Department (G.C., V.F., L.H., F.H., M.J.S., Y.S., C.E., M.H., S.C., D.R., M.J.P., F.K.S., M.N.), Harvard Medical School, Boston. 2. Massachusetts General Hospital and Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics (J.P.), Harvard Medical School, Boston. 3. Center for Regenerative Medicine, Massachusetts General Hospital, Boston (N.S., D.T.S.). 4. Harvard Stem Cell Institute, Cambridge, MA (N.S., D.T.S.). 5. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (N.S., D.T.S.). 6. Molecular Imaging and Neurovascular Research Laboratory, Department of Neurology, Dongguk University College of Medicine, Goyang, South Korea (D.-E.K.). 7. Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown (M.A.M.). 8. Cardiovascular Research Center (M.N.), Harvard Medical School, Boston.
Abstract
RATIONALE: After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow. OBJECTIVE: To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke. METHODS AND RESULTS: We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88-/- and TLR4-/- mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers. CONCLUSIONS: Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.
RATIONALE: After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow. OBJECTIVE: To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke. METHODS AND RESULTS: We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88-/- and TLR4-/- mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1miceattenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers. CONCLUSIONS: Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.
Authors: Gabriel Courties; Fanny Herisson; Hendrik B Sager; Timo Heidt; Yuxiang Ye; Ying Wei; Yuan Sun; Nicolas Severe; Partha Dutta; Jennifer Scharff; David T Scadden; Ralph Weissleder; Filip K Swirski; Michael A Moskowitz; Matthias Nahrendorf Journal: Circ Res Date: 2014-10-31 Impact factor: 17.367
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