Skip to main content
Log in

Impact of acquired and innate immunity on spinal cord ischemia and reperfusion injury

General Thoracic and Cardiovascular Surgery Aims and scope Submit manuscript

Cite this article



The aim of this study was to clarify the impact of acquired and innate immunity on spinal cord ischemia and reperfusion injury using a mouse model of spinal cord ischemia.


To define the ischemic duration that caused paraplegia, wild-type and severe combined immunodeficiency (SCID) mice were subjected to cross-clamping of the aorta for 7, 9, 9.5, or 10.5 min with ischemic preconditioning for intestinal protection. In wild-type and SCID mice with paraplegia, histological analyses were performed to investigate viable neurons, inflammatory cells, and reactive astrocytes at 12, 24, 48, and 72 h as well as 7 days after reperfusion.


In both wild-type and SCID mice, immediate paraplegia was induced by occlusion for 10.5 min. In both wild-type and SCID mice, no infiltration of T or B lymphocytes was observed at any point after reperfusion, but reactive astrocytes were clearly visible at 7 days after reperfusion, and the number of activated microglia peaked at 12 and 48 h after reperfusion. Although there was no significant difference, wild-type mice had a tendency to have more activated microglia than SCID mice at 12 h after reperfusion, and to have less viable neurons than SCID mice at 12, 24, 48, and 72 h after reperfusion. There was a tendency that the frequency of immediate paraplegia in wild-type mice was more than SCID mice though no statistical difference was observed.


Innate immunity, rather than acquired immunity, may be involved in the developing immediate paraplegia in our mouse model.

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

Access this article

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



Blood brain barrier


Ischemic preconditioning


Ischemic reperfusion injury


Left subclavian artery


Spinal cord ischemia


Severe combined immunodeficiency


Basso mouse scale


Toll-like receptor


  1. Committee for Scientific Affairs TJAfTS, Masuda M, Kuwano H, Okumura M, Amano J, Arai H, et al. Thoracic and cardiovascular surgery in Japan during 2012: annual report by The Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg. 2014;62(12):734–64.

    Article  Google Scholar 

  2. Jander S, Kraemer M, Schroeter M, Witte OW, Stoll G. Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. J Cereb Blood Flow Metab. 1995;15(1):42–51.

    Article  CAS  PubMed  Google Scholar 

  3. Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15(8):946–50.

    Article  CAS  PubMed  Google Scholar 

  4. Lang-Lazdunski L, Matsushita K, Hirt L, Waeber C, Vonsattel JP, Moskowitz MA, et al. Spinal cord ischemia. Development of a model in the mouse. Stroke. 2000;31(1):208–13.

    Article  CAS  PubMed  Google Scholar 

  5. Kakinohana M, Kida K, Minamishima S, Atochin DN, Huang PL, Kaneki M, et al. Delayed paraplegia after spinal cord ischemic injury requires caspase-3 activation in mice. Stroke. 2011;42(8):2302–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, Popovich PG. Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma. 2006;23(5):635–59.

    Article  PubMed  Google Scholar 

  7. Okita Y. Fighting spinal cord complication during surgery for thoracoabdominal aortic disease. Gen Thorac Cardiovasc Surg. 2011;59(2):79–90.

    Article  PubMed  Google Scholar 

  8. Linfert D, Chowdhry T, Rabb H. Lymphocytes and ischemia-reperfusion injury. Transpl Rev (Orlando). 2009;23(1):1–10.

    Article  Google Scholar 

  9. Hurn PD, Subramanian S, Parker SM, Afentoulis ME, Kaler LJ, Vandenbark AA, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab. 2007;27(11):1798–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liesz A, Zhou W, Mracsko E, Karcher S, Bauer H, Schwarting S, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain. 2011;134(Pt 3):704–20.

    Article  PubMed  Google Scholar 

  11. Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP. Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience. 2009;158(3):1007–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tachibana T, Shiiya N, Kunihara T, Wakamatsu Y, Kudo AF, Ooka T, et al. Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits. J Thorac Cardiovasc Surg. 2005;129(1):123–8.

    Article  CAS  PubMed  Google Scholar 

  13. Chiesa R, Melissano G, Marrocco-Trischitta M, Civilini E, Setacci F. Spinal cord ischemia after elective stent-graft repair of the thoracic aorta. J Vasc Surg. 2005;42(1):11–7.

    Article  PubMed  Google Scholar 

  14. Spera PA, Ellison JA, Feuerstein GZ, Barone FC. IL-10 reduces rat brain injury following focal stroke. Neurosci Lett. 1998;251(3):189–92.

    Article  CAS  PubMed  Google Scholar 

  15. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, et al. Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA. 1997;94(5):2007–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173(6):3916–24.

    Article  CAS  PubMed  Google Scholar 

  17. Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002;168(2):554–61.

    Article  CAS  PubMed  Google Scholar 

  18. Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol. 2007;190(1–2):28–33.

    Article  CAS  PubMed  Google Scholar 

  19. Brea D, Blanco M, Ramos-Cabrer P, Moldes O, Arias S, Perez-Mato M, et al. Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values. J Cereb Blood Flow Metab. 2011;31(6):1424–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bell MT, Puskas F, Agoston VA, Cleveland JC Jr, Freeman KA, Gamboni F, et al. Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury. Circulation. 2013;128(11 Suppl 1):S152–6.

    Article  CAS  PubMed  Google Scholar 

  21. Abbott NJ. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat. 2002;200(6):629–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kaur C, Ling EA. Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res. 2008;5(1):71–81.

    Article  CAS  PubMed  Google Scholar 

  23. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69.

    Article  CAS  PubMed  Google Scholar 

  24. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8.

    Article  CAS  PubMed  Google Scholar 

  25. Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol. 1998;56(2):149–71.

    Article  CAS  PubMed  Google Scholar 

  26. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med. 2006;203(7):1685–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Burghaus L, Hilker R, Thiel A, Galldiks N, Lehnhardt FG, Zaro-Weber O, et al. Deep brain stimulation of the subthalamic nucleus reversibly deteriorates stuttering in advanced Parkinson’s disease. J Neural Transm. 2006;113(5):625–31.

    Article  CAS  PubMed  Google Scholar 

  28. Smith PD, Puskas F, Meng X, Lee JH, Cleveland JC Jr, Weyant MJ, et al. The evolution of chemokine release supports a bimodal mechanism of spinal cord ischemia and reperfusion injury. Circulation. 2012;126(11 Suppl 1):S110–7.

    Article  CAS  PubMed  Google Scholar 

Download references


We wish to thank Dr. Manabu Kakinohana (Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus), Dr. Akiko Tanaka (Department of Surgery, Section of Cardiac and Thoracic Surgery, University of Chicago) and Dr. Hisatomo Kowa (Division of Neurology, Kobe University Graduate School of Medicine) for their kind support.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Katsuhiro Yamanaka.

Ethics declarations

Conflict of interest

Katsuhiro Yamanaka and other co-authors have 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

Yamanaka, K., Sasaki, N., Fujita, Y. et al. Impact of acquired and innate immunity on spinal cord ischemia and reperfusion injury. Gen Thorac Cardiovasc Surg 64, 251–259 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: