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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Splenic responses play an important role in remote ischemic preconditioning-mediated neuroprotection against stroke

Authors: Chen Chen, Wei Jiang, Zongjian Liu, Fengwu Li, Jian Yang, Yanlong Zhao, Yuanyuan Ran, Yan Meng, Xunming Ji, Xiaokun Geng, Huishan Du, Xiaoming Hu

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Remote ischemic preconditioning (RIPC) of a limb has been reported to protect against ischemic stroke. Our previous results demonstrated that the RIPC-mediated neuroprotection is associated with alterations in circulating immune cell populations. Here, we evaluated the effect of the spleen, the largest reservoir of immune cells, on RIPC-mediated neuroprotection against stroke.

Methods

Noninvasive RIPC was achieved by four repeated cycles of 5-min blood flow constriction in the hindlimbs using a tourniquet. The blood and spleens were collected before and 1 h and 3 days after preconditioning to analyze the effect of RIPC on the spleen and the correlation between splenic and peripheral lymphocytes. Moreover, spleen weight and splenic lymphocytes were compared in stroke rats with or without RIPC. Finally, splenectomy was made 1 day or 2 weeks before RIPC and 90-min middle cerebral artery occlusion (MCAO). The infarct areas and deficits were assessed. Blood was collected 1 h after RIPC and 3 days after MCAO to explore the impact of splenectomy on RIPC-induced neuroprotection and immune changes. The contralateral and ipsilateral hemispheres were collected 3 days after MCAO to detect the infiltration of immune cells after RIPC and splenectomy.

Results

Flow cytometry analysis demonstrated that the RIPC promptly increased the percentages of CD3+CD8+ cytotoxic T (Tc) cells in the spleen with a relatively delayed elevation in CD3+CD161+ natural killer T (NKT) and CD3−CD45RA+ B lymphocytes. The percentages of circulating lymphocytes are positively correlated with the percentages of splenic lymphocytes in normal rats. Interestingly, RIPC resulted in negative correlations between the percentages of splenic and circulating T lymphocytes, while the correlation between splenic and circulating B lymphocytes remained positive. For animals subjected to RIPC followed by MCAO, RIPC increased splenic volume with an expansion of splenic lymphocytes 3 days after MCAO. Furthermore, the removal of the spleen 1 day or 2 weeks before RIPC and MCAO reduced the protective effect of RIPC on ischemic brain injury and reversed the effects of RIPC on circulating immune cell composition. RIPC significantly reduced brain infiltration of Tc and NKT cells. Prior splenectomy showed no effect on immune cell infiltration after RIPC and stroke.

Conclusion

These results reveal an immunomodulatory effect of the spleen, effecting mainly the spleen-derived lymphocytes, during RIPC-afforded neuroprotection against cerebral ischemia.
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Literature
1.
Hess DC, Hoda MN, Bhatia K. Remote limb perconditioning [corrected] and postconditioning: will it translate into a promising treatment for acute stroke? Stroke. 2013;44:1191–7.CrossRefPubMed
2.
Wang Y, Reis C, Applegate R 2nd, Stier G, Martin R, Zhang JH. Ischemic conditioning-induced endogenous brain protection: applications pre-, per- or post-stroke. Exp Neurol. 2015;272:26–40.CrossRefPubMedPubMedCentral
3.
Li S, Hafeez A, Noorulla F, Geng X, Shao G, Ren C, Lu G, Zhao H, Ding Y, Ji X. Preconditioning in neuroprotection: from hypoxia to ischemia. Prog Neurobiol. 2017;157:79–91.
4.
Hess DC, Blauenfeldt RA, Andersen G, Hougaard KD, Hoda MN, Ding Y, Ji X. Remote ischaemic conditioning-a new paradigm of self-protection in the brain. Nat Rev Neurol. 2015;11:698–710.CrossRefPubMed
5.
Meller R, Simon RP. A critical review of mechanisms regulating remote preconditioning-induced brain protection. J Appl Physiol (1985). 2015;119:1135–42.CrossRef
6.
Hu S, Dong H, Zhang H, Wang S, Hou L, Chen S, Zhang J, Xiong L. Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats. Brain Res. 2012;1459:81–90.CrossRefPubMed
7.
Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, Li G, Ren C, Luo Y, Ling F, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 2012;79:1853–61.CrossRefPubMed
8.
Liu ZJ, Chen C, Li XR, Ran YY, Xu T, Zhang Y, Geng XK, Zhang Y, Du HS, Leak RK, et al. Remote ischemic preconditioning-mediated neuroprotection against stroke is associated with significant alterations in peripheral immune responses. CNS Neurosci Ther. 2016;22:43–52.CrossRefPubMed
9.
Tulu S, Mulino M, Pinggera D, Luger M, Wurtinger P, Grams A, Bodner T, Beer R, Helbok R, Matteucci-Gothe R, et al. Remote ischemic preconditioning in the prevention of ischemic brain damage during intracranial aneurysm treatment (RIPAT): study protocol for a randomized controlled trial. Trials. 2015;16:594.CrossRefPubMedPubMedCentral
10.
Connolly M, Bilgin-Freiert A, Ellingson B, Dusick JR, Liebeskind D, Saver J, Gonzalez NR. Peripheral vascular disease as remote ischemic preconditioning, for acute stroke. Clin Neurol Neurosurg. 2013;115:2124–9.CrossRefPubMedPubMedCentral
11.
Wang S, Zhang H, Xu Y. Crosstalk between microglia and T cells contributes to brain damage and recovery after ischemic stroke. Neurol Res. 2016;38:495–503.CrossRefPubMed
12.
Selvaraj UM, Poinsatte K, Torres V, Ortega SB, Stowe AM. Heterogeneity of B cell functions in stroke-related risk, prevention, injury, and repair. Neurotherapeutics. 2016;13:729–47.CrossRefPubMedPubMedCentral
13.
Gan Y, Liu Q, Wu W, Yin JX, Bai XF, Shen R, Wang Y, Chen J, La Cava A, Poursine-Laurent J, et al. Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci U S A. 2014;111:2704–9.CrossRefPubMedPubMedCentral
14.
Vahidy FS, Parsha KN, Rahbar MH, Lee M, Bui TT, Nguyen C, Barreto AD, Bambhroliya AB, Sahota P, Yang B, et al. Acute splenic responses in patients with ischemic stroke and intracerebral hemorrhage. J Cereb Blood Flow Metab. 2016;36:1012–21.CrossRefPubMed
15.
Sahota P, Vahidy F, Nguyen C, Bui TT, Yang B, Parsha K, Garrett J, Bambhroliya A, Barreto A, Grotta JC, et al. Changes in spleen size in patients with acute ischemic stroke: a pilot observational study. Int J Stroke. 2013;8:60–7.CrossRefPubMed
16.
Seifert HA, Hall AA, Chapman CB, Collier LA, Willing AE, Pennypacker KR. A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation. J NeuroImmune Pharmacol. 2012;7:1017–24.CrossRefPubMedPubMedCentral
17.
Liu ZJ, Chen C, Li FW, Shen JM, Yang YY, Leak RK, Ji XM, Du HS, Hu XM. Splenic responses in ischemic stroke: new insights into stroke pathology. CNS Neurosci Ther. 2015;21:320–6.CrossRefPubMed
18.
Chiu NL, Kaiser B, Nguyen YV, Welbourne S, Lall C, Cramer SC. The volume of the spleen and its correlates after acute stroke. J Stroke Cerebrovasc Dis. 2016;25:2958–61.CrossRefPubMedPubMedCentral
19.
Hu X, Lu Y, Zhang Y, Li Y, Jiang L. Remote ischemic preconditioning improves spatial learning and memory ability after focal cerebral ischemia-reperfusion in rats. Perfusion. 2013;28:546–51.CrossRefPubMed
20.
Zwagerman N, Plumlee C, Guthikonda M, Ding Y. Toll-like receptor-4 and cytokine cascade in stroke after exercise. Neurol Res. 2010;32:123–6.CrossRefPubMed
21.
Ren C, Gao M, Dornbos D 3rd, Ding Y, Zeng X, Luo Y, Ji X. Remote ischemic post-conditioning reduced brain damage in experimental ischemia/reperfusion injury. Neurol Res. 2011;33:514–9.CrossRefPubMed
22.
Viboolvorakul S, Patumraj S. Exercise training could improve age-related changes in cerebral blood flow and capillary vascularity through the upregulation of VEGF and eNOS. Biomed Res Int. 2014;2014:230791.CrossRefPubMedPubMedCentral
23.
Kimbler DE, Shields J, Yanasak N, Vender JR, Dhandapani KM. Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice. PLoS One. 2012;7:e41229.CrossRefPubMedPubMedCentral
24.
Fan QY, Liu JJ, Zhang GL, Wu HQ, Zhang R, Zhan SQ, Liu N. Inhibition of SNK-SPAR signaling pathway promotes the restoration of motor function in a rat model of ischemic stroke. J Cell Biochem. 2018;119:1093–110.CrossRefPubMed
25.
Feng Y, Liao S, Wei C, Jia D, Wood K, Liu Q, Wang X, Shi FD, Jin WN. Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models. J Neuroinflammation. 2017;14:248.CrossRefPubMedPubMedCentral
26.
Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol. 2006;66:232–45.CrossRefPubMed
27.
Ross AM, Hurn P, Perrin N, Wood L, Carlini W, Potempa K. Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis. 2007;16:203–7.CrossRefPubMed
28.
29.
Blomster LV, Brennan FH, Lao HW, Harle DW, Harvey AR, Ruitenberg MJ. Mobilisation of the splenic monocyte reservoir and peripheral CX(3)CR1 deficiency adversely affects recovery from spinal cord injury. Exp Neurol. 2013;247:226–40.CrossRefPubMed
30.
Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, Hong NH, Kim JH, Ban JJ, Park HK, et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 2008;131:616–29.CrossRefPubMed
31.
Li M, Li F, Luo C, Shan Y, Zhang L, Qian Z, Zhu G, Lin J, Feng H. Immediate splenectomy decreases mortality and improves cognitive function of rats after severe traumatic brain injury. J Trauma. 2011;71:141–7.CrossRefPubMed
32.
Walker PA, Shah SK, Jimenez F, Gerber MH, Xue H, Cutrone R, Hamilton JA, Mays RW, Deans R, Pati S, et al. Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes. Exp Neurol. 2010;225:341–52.CrossRefPubMedPubMedCentral
33.
Yang B, Hamilton JA, Valenzuela KS, Bogaerts A, Xi X, Aronowski J, Mays RW, Savitz SI. Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells. 2017;35:1290–302.CrossRefPubMed
34.
Zhang BJ, Men XJ, Lu ZQ, Li HY, Qiu W, Hu XQ. Splenectomy protects experimental rats from cerebral damage after stroke due to anti-inflammatory effects. Chin Med J. 2013;126:2354–60.PubMed
35.
Seifert HA, Leonardo CC, Hall AA, Rowe DD, Collier LA, Benkovic SA, Willing AE, Pennypacker KR. The spleen contributes to stroke induced neurodegeneration through interferon gamma signaling. Metab Brain Dis. 2012;27:131–41.CrossRefPubMedPubMedCentral
36.
Ajmo CT Jr, Vernon DO, Collier L, Hall AA, Garbuzova-Davis S, Willing A, Pennypacker KR. The spleen contributes to stroke-induced neurodegeneration. J Neurosci Res. 2008;86:2227–34.CrossRefPubMedPubMedCentral
37.
Kim E, Yang J, Beltran CD, Cho S. Role of spleen-derived monocytes/macrophages in acute ischemic brain injury. J Cereb Blood Flow Metab. 2014;34:1411–9.CrossRefPubMedPubMedCentral
38.
Pennypacker KR, Offner H. The role of the spleen in ischemic stroke. J Cereb Blood Flow Metab. 2015;35:186–7.CrossRefPubMed
39.
Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, Offner H. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007;27:1798–805.CrossRefPubMedPubMedCentral
40.
Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, Austinat M, Nieswandt B, Wiendl H, Stoll G. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood. 2010;115:3835–42.CrossRefPubMed
41.
42.
Kang SJ, Liang HE, Reizis B, Locksley RM. Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells. Immunity. 2008;29:819–33.CrossRefPubMedPubMedCentral
43.
Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7:311–7.CrossRefPubMed
44.
Auffray C, Fogg DK, Narni-Mancinelli E, Senechal B, Trouillet C, Saederup N, Leemput J, Bigot K, Campisi L, Abitbol M, et al. CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J Exp Med. 2009;206:595–606.CrossRefPubMedPubMedCentral
45.
Norris BA, Uebelhoer LS, Nakaya HI, Price AA, Grakoui A, Pulendran B. Chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific T cell immunity. Immunity. 2013;38:309–21.CrossRefPubMed
46.
Bodhankar S, Chen Y, Vandenbark AA, Murphy SJ, Offner H. IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. Metab Brain Dis. 2013;28:375–86.CrossRefPubMedPubMedCentral
47.
Ren X, Akiyoshi K, Dziennis S, Vandenbark AA, Herson PS, Hurn PD, Offner H. Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J Neurosci. 2011;31:8556–63.CrossRefPubMedPubMedCentral
48.
Monson NL, Ortega SB, Ireland SJ, Meeuwissen AJ, Chen D, Plautz EJ, Shubel E, Kong X, Li MK, Freriks LH, Stowe AM. Repetitive hypoxic preconditioning induces an immunosuppressed B cell phenotype during endogenous protection from stroke. J Neuroinflammation. 2014;11:22.CrossRefPubMedPubMedCentral
49.
Doyle KP, Quach LN, Sole M, Axtell RC, Nguyen TV, Soler-Llavina GJ, Jurado S, Han J, Steinman L, Longo FM, et al. B-lymphocyte-mediated delayed cognitive impairment following stroke. J Neurosci. 2015;35:2133–45.CrossRefPubMedPubMedCentral
Metadata
Title
Splenic responses play an important role in remote ischemic preconditioning-mediated neuroprotection against stroke
Authors
Chen Chen
Wei Jiang
Zongjian Liu
Fengwu Li
Jian Yang
Yanlong Zhao
Yuanyuan Ran
Yan Meng
Xunming Ji
Xiaokun Geng
Huishan Du
Xiaoming Hu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1190-9

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