Cerebral ischemia increases bone marrow CD4+CD25+FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system
Authors: Xi Liu
Chao Jiang
Jianping Wang
Lie Yu
Jian Wang
Chunying Ou
Xiaojie Fu
Xiaobing Cui
Chengguang Zhou
Menghan Wang
Journal: Brain Behavior and Immunity (2015)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Bone marrow; Cerebral ischemia; Immunosuppression; RANKL; SDF-1
Affiliations: Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address: ., Department of Neurology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China., 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., Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address: .

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. 

Retracted: No

PubPeer comments:
 Fig 2H has many overlaps, I only was patient enough to mark very few of them ![file] , 
 Fig 3G. It can be a reasonable guess that only the FACS of Buto might be from a different experiment. Similar manipulations can be seen in FIgs 4, 5, and 6. I ran out of patience marking them. ![file] , 
 No wonder. There s been an [EOC by the journal in March] The editors of Brain Behaviour and Immunity issue this expression of concern regarding the above papers for the following reasons: - there appears to be multiple instances of duplication of the same figures, or part of figures (quadrants) illustrating the flowcytometry patterns under different experimental conditions; - a new independent referee has examined the paper and has expressed similar concerns; - we have received no reply to our repeated requests for clarifications from the senior author or other authors involved in the publications. At this stage it is impossible to determine if these are genuine mistakes or evidence of scientific misconduct, but the duplication of figure raises concerns on the accuracy of the conclusions reached by the paper. , 
  it is impossible to determine if these are genuine mistakes or evidence of scientific misconduct . I d like to add Figure 1H from my archives. ![file] ,