title: Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system.
abstract: Recent evidence has shown that an increase in CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells may contribute to stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that stroke activates the sympathetic nervous system, which was abolished by 6-OHDA. The consequent activation of β2-adrenergic receptor (AR) signaling increased prostaglandin E2 (PGE2) level in bone marrow. β2-AR antagonist prevented the upregulation of PGE2. PGE2, which acts on prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-κB ligand (RANKL) in CD4(+) T cells and mediated the increase in Treg cells in bone marrow. Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells. PGE2 also elevated the expression of indoleamine 2,3 dioxygenase in CD11C(+) dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with indomethacin. Concurrently, stroke reduced production of stromal cell-derived factor-1 (SDF-1) via β3-AR signals in bone marrow but increased the expression of C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with β3-AR antagonist SR-59230A reduced the percent of Treg cells in peripheral blood after stroke. The disruption of the CXCR4-SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4(+) cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after stroke. We conclude that cerebral ischemia can increase bone marrow CD4(+)CD25(+)FoxP3(+) regulatory T cells via signals from the sympathetic nervous system.
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address: wjpwfy666@126.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Lie
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Menghan
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Ou
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Chengguang
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address: jwang79@jhmi.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D002545:Brain Ischemia / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D008297:Male; D051379:Mice; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013564:Sympathetic Nervous System / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone
keywords: Bone marrow; Cerebral ischemia; Immunosuppression; RANKL; SDF-1; SNS; Treg cells
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