Skip to main content

Advertisement

SpringerLink
Log in

Adoptive Regulatory T-cell Therapy Attenuates Perihematomal Inflammation in a Mouse Model of Experimental Intracerebral Hemorrhage

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The CD4+CD25+ regulatory T cells (Tregs), an innate immunomodulator, suppress cerebral inflammation and maintain immune homeostasis in multiple central nervous system injury, but its role in intracerebral hemorrhage (ICH) has not been fully characterized. This study investigated the effect of Tregs on brain injury using the mouse ICH model, which is established by autologous blood infusion. The results showed that tail intravenous injection of Tregs significantly reduced brain water content and Evans blue dye extravasation of perihematoma at day (1, 3 and 7), and improved short- and long-term neurological deficits following ICH in mouse model. Tregs treatment reduced the content of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and malondialdehyde, while increasing the superoxide dismutase (SOD) enzymatic activity at day (1, 3 and 7) following ICH. Furthermore, Tregs treatment obviously reduced the number of NF-κB+, IL-6+, TUNEL+ and active caspase-3+ cells at day 3 after ICH. These results indicate that adoptive transfer of Tregs may provide neuroprotection following ICH in mouse models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Aronowski J, Hall CE (2005) New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 27(3):268–279. doi:10.1179/016164105X25225

    Article  PubMed  Google Scholar 

  • Castillo J, Davalos A, Alvarez-Sabin J, Pumar JM, Leira R, Silva Y, Montaner J, Kase CS (2002) Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58(4):624–629

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Yang Q, Chen G, Zhang JH (2015) An update on inflammation in the acute phase of intracerebral hemorrhage. Transl Stroke Res 6(1):4–8. doi:10.1007/s12975-014-0384-4

    Article  CAS  PubMed  Google Scholar 

  • Duan X, Wen Z, Shen H, Shen M, Chen G (2016) Intracerebral hemorrhage, oxidative stress, and antioxidant therapy. Oxidative Med Cell Longev 2016:1203285. doi:10.1155/2016/1203285

    Article  Google Scholar 

  • Galho AR, Cordeiro MF, Ribeiro SA, Marques MS, Antunes MF, Luz DC, Hadrich G, Muccillo-Baisch AL, Barros DM, Lima JV, Dora CL, Horn AP (2016) Protective role of free and quercetin-loaded nanoemulsion against damage induced by intracerebral haemorrhage in rats. Nanotechnology 27(17):175101. doi:10.1088/0957-4484/27/17/175101

    Article  CAS  PubMed  Google Scholar 

  • Hickenbottom SL, Grotta JC, Strong R, Denner LA, Aronowski J (1999) Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage in rats. Stroke 30(11):2472–2477 (discussion 2477–2478)

    Article  CAS  PubMed  Google Scholar 

  • Holmin S, Mathiesen T (2000) Intracerebral administration of interleukin-1beta and induction of inflammation, apoptosis, and vasogenic edema. J Neurosurg 92(1):108–120. doi:10.3171/jns.2000.92.1.0108

    Article  CAS  PubMed  Google Scholar 

  • Hu X, Tao C, Gan Q, Zheng J, Li H, You C (2016) Oxidative stress in intracerebral hemorrhage: sources, mechanisms, and therapeutic targets. Oxidative Med Cell Longev 2016:3215391. doi:10.1155/2016/3215391

    Google Scholar 

  • Hua Y, Wu J, Keep RF, Nakamura T, Hoff JT, Xi G (2006) Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery 58(3):542–550. doi:10.1227/01.NEU.0000197333.55473.AD (discussion 542–550)

    Article  PubMed  Google Scholar 

  • Hwang BY, Appelboom G, Ayer A, Kellner CP, Kotchetkov IS, Gigante PR, Haque R, Kellner M, Connolly ES (2011) Advances in neuroprotective strategies: potential therapies for intracerebral hemorrhage. Cerebrovasc Dis 31(3):211–222. doi:10.1159/000321870

    Article  PubMed  Google Scholar 

  • Joice SL, Mydeen F, Couraud PO, Weksler BB, Romero IA, Fraser PA, Easton AS (2009) Modulation of blood-brain barrier permeability by neutrophils: in vitro and in vivo studies. Brain Res 1298:13–23. doi:10.1016/j.brainres.2009.08.076

    Article  CAS  PubMed  Google Scholar 

  • Keep RF, Hua Y, Xi G (2012) Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol 11(8):720–731. doi:10.1016/S1474-4422(12)70104-7

    Article  CAS  PubMed  Google Scholar 

  • Krafft PR, McBride DW, Lekic T, Rolland WB, Mansell CE, Ma Q, Tang J, Zhang JH (2014) Correlation between subacute sensorimotor deficits and brain edema in two mouse models of intracerebral hemorrhage. Behav Brain Res 264:151–160. doi:10.1016/j.bbr.2014.01.052

    Article  PubMed  PubMed Central  Google Scholar 

  • Li P, Gan Y, Sun BL, Zhang F, Lu B, Gao Y, Liang W, Thomson AW, Chen J, Hu X (2013a) Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann Neurol 74(3):458–471. doi:10.1002/ana.23815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li P, Mao L, Zhou G, Leak RK, Sun BL, Chen J, Hu X (2013b) Adoptive regulatory T-cell therapy preserves systemic immune homeostasis after cerebral ischemia. Stroke 44(12):3509–3515. doi:10.1161/STROKEAHA.113.002637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liesz A, Kleinschnitz C (2016) Regulatory T cells in post-stroke immune homeostasis. Transl Stroke Res 7(4):313–321. doi:10.1007/s12975-016-0465-7

    Article  CAS  PubMed  Google Scholar 

  • Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15(2):192–199. doi:10.1038/nm.1927

    Article  CAS  PubMed  Google Scholar 

  • Lin S, Yin Q, Zhong Q, Lv FL, Zhou Y, Li JQ, Wang JZ, Su BY, Yang QW (2012) Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflamm 9:46. doi:10.1186/1742-2094-9-46

    CAS  Google Scholar 

  • Megyeri P, Abraham CS, Temesvari P, Kovacs J, Vas T, Speer CP (1992) Recombinant human tumor necrosis factor alpha constricts pial arterioles and increases blood-brain barrier permeability in newborn piglets. Neurosci Lett 148(1–2):137–140

    Article  CAS  PubMed  Google Scholar 

  • Murthy SB, Moradiya Y, Dawson J, Lees KR, Hanley DF, Ziai WC, Collaborators V-I (2015) Perihematomal edema and functional outcomes in intracerebral hemorrhage: influence of hematoma volume and location. Stroke 46(11):3088–3092. doi:10.1161/STROKEAHA.115.010054

    Article  PubMed  Google Scholar 

  • Nag S, Manias JL, Stewart DJ (2009) Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 118(2):197–217. doi:10.1007/s00401-009-0541-0

    Article  PubMed  Google Scholar 

  • Nguyen HX, O’Barr TJ, Anderson AJ (2007) Polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and TNF-alpha. J Neurochem 102(3):900–912. doi:10.1111/j.1471-4159.2007.04643.x

    Article  CAS  PubMed  Google Scholar 

  • Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD (2006) Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 26(5):654–665. doi:10.1038/sj.jcbfm.9600217

    Article  CAS  PubMed  Google Scholar 

  • Rynkowski MA, Kim GH, Komotar RJ, Otten ML, Ducruet AF, Zacharia BE, Kellner CP, Hahn DK, Merkow MB, Garrett MC, Starke RM, Cho BM, Sosunov SA, Connolly ES (2008) A mouse model of intracerebral hemorrhage using autologous blood infusion. Nat Protoc 3(1):122–128. doi:10.1038/nprot.2007.513

    Article  CAS  PubMed  Google Scholar 

  • Shi L, Qin J, Song B, Wang QM, Zhang R, Liu X, Liu Y, Hou H, Chen X, Ma X, Jiang C, Sun X, Gong G, Xu Y (2015) Increased frequency of circulating regulatory T cells in patients with acute cerebral hemorrhage. Neurosci Lett 591:115–120. doi:10.1016/j.neulet.2015.02.042

    Article  CAS  PubMed  Google Scholar 

  • Stubbe T, Ebner F, Richter D, Engel O, Klehmet J, Royl G, Meisel A, Nitsch R, Meisel C, Brandt C (2013) Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO. J Cereb Blood Flow Metab 33(1):37–47. doi:10.1038/jcbfm.2012.128

    Article  CAS  PubMed  Google Scholar 

  • Taylor RA, Sansing LH (2013) Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013:746068. doi:10.1155/2013/746068

    Article  PubMed  PubMed Central  Google Scholar 

  • Urday S, Beslow LA, Dai F, Zhang F, Battey TW, Vashkevich A, Ayres AM, Leasure AC, Selim MH, Simard JM, Rosand J, Kimberly WT, Sheth KN (2016) Rate of perihematomal edema expansion predicts outcome after intracerebral hemorrhage. Crit Care Med 44(4):790–797. doi:10.1097/CCM.0000000000001553

    PubMed  PubMed Central  Google Scholar 

  • Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8(7):523–532. doi:10.1038/nri2343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wakai T, Narasimhan P, Sakata H, Wang E, Yoshioka H, Kinouchi H, Chan PH (2015) Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab. doi:10.1177/0271678X15613798

    PubMed  Google Scholar 

  • Wang Y, Mao L, Zhang L, Zhang L, Yang M, Zhang Z, Li D, Fan C, Sun B (2016) Adoptive regulatory T-cell therapy attenuates subarachnoid hemorrhage-induced cerebral inflammation by suppressing TLR4/NF-B signaling pathway. Curr Neurovasc Res 13(2):121–126

    Article  CAS  PubMed  Google Scholar 

  • Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11(1):7–13. doi:10.1038/ni.1818

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Yang S, Xi G, Song S, Fu G, Keep RF, Hua Y (2008) Microglial activation and brain injury after intracerebral hemorrhage. Acta Neurochir Suppl 105:59–65

    Article  CAS  PubMed  Google Scholar 

  • Yan J, Greer JM, Etherington K, Cadigan GP, Cavanagh H, Henderson RD, O’Sullivan JD, Pandian JD, Read SJ, McCombe PA (2009) Immune activation in the peripheral blood of patients with acute ischemic stroke. J Neuroimmunol 206(1–2):112–117. doi:10.1016/j.jneuroim.2008.11.001

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Yu A, Liu Y, Shen H, Lin C, Lin L, Wang S, Yuan B (2014) Regulatory T cells inhibit microglia activation and protect against inflammatory injury in intracerebral hemorrhage. Int Immunopharmacol 22(2):522–525. doi:10.1016/j.intimp.2014.06.037

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Schallert T, Zhang ZG, Jiang Q, Arniego P, Li Q, Lu M, Chopp M (2002) A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. J Neurosci Methods 117(2):207–214

    Article  PubMed  Google Scholar 

  • Zhang ZY, Jiang M, Fang J, Yang MF, Zhang S, Yin YX, Li DW, Mao LL, Fu XY, Hou YJ, Fu XT, Fan CD, Sun BL (2015a) Enhanced therapeutic potential of nano-curcumin against subarachnoid hemorrhage-induced blood–brain barrier disruption through inhibition of inflammatory response and oxidative stress. Mol Neurobiol. doi:10.1007/s12035-015-9635-y

    Google Scholar 

  • Zhang ZY, Sun BL, Yang MF, Li DW, Fang J, Zhang S (2015b) Carnosine attenuates early brain injury through its antioxidative and anti-apoptotic effects in a rat experimental subarachnoid hemorrhage model. Cell Mol Neurobiol 35(2):147–157. doi:10.1007/s10571-014-0106-1

    Article  PubMed  Google Scholar 

  • Zhao X, Zhang Y, Strong R, Zhang J, Grotta JC, Aronowski J (2007) Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem 101(3):652–663. doi:10.1111/j.1471-4159.2006.04414.x

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW (2014) Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol 115:25–44. doi:10.1016/j.pneurobio.2013.11.003

    Article  CAS  PubMed  Google Scholar 

  • Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, Zhu WY, Liao MF, Wu LR, Yang YR, Liu J, Duan CM, Li J, Gong QW, Liu L, Yang MH, Xiong A, Wang J, Yang QW (2016) Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3beta/PTEN axis. J Cereb Blood Flow Metab. doi:10.1177/0271678X16648712

    PubMed Central  Google Scholar 

Download references

Acknowledgments

The national natural science foundation of China (NSFC) (Nos. 81471212 and 81301018) and natural science foundation of Shandong province of China (No. ZR2014HQ027) supported this work.

Authors’ contributors

ZZ, XY and BS conceived the project and designed experiments. LM, HY, WW, YW, and MY performed the experiment. LM, ZZ and BS analyzed the results. ZZ wrote the manuscript with contributions from LM, BS and XY. XY revised the manuscript.

Author information

Authors and Affiliations

  1. Key Lab of Cerebral Microcirculation at the Universities of Shandong, Life Science Research Centre of Taishan Medical University, Taian, 271016, Shandong, China

    Lei-Lei Mao, Hui Yuan, Wen-wen Wang, Yu-jing Wang, Ming-feng Yang, Bao-liang Sun, Zong-yong Zhang & Xiao-yi Yang

  2. Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, 271016, Shandong, China

    Hui Yuan & Bao-liang Sun

Authors
  1. Lei-Lei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-wen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-jing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming-feng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bao-liang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zong-yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiao-yi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zong-yong Zhang or Xiao-yi Yang.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, LL., Yuan, H., Wang, Ww. et al. Adoptive Regulatory T-cell Therapy Attenuates Perihematomal Inflammation in a Mouse Model of Experimental Intracerebral Hemorrhage. Cell Mol Neurobiol 37, 919–929 (2017). https://doi.org/10.1007/s10571-016-0429-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-016-0429-1

Keywords

Search

Navigation