Skip to main content
PMC home page
Journal of Cerebral Blood Flow & Metabolism logoLink to Journal of Cerebral Blood Flow & Metabolism
letter
. 2014 Dec 3;35(2):186–187. doi: 10.1038/jcbfm.2014.212

The role of the spleen in ischemic stroke

Keith R Pennypacker 1,*, Halina Offner 2
PMCID: PMC4426754  PMID: 25465042

Abstract

This opinion piece highlights the scientific literature reporting that the peripheral immune response to ischemic stroke originates from the spleen. Removal of the spleen not only reduces stroke-induced neurodegeneration but also cellular degeneration in the body's other tissues when exposed to ischemic conditions.

Keywords: brain ischemia, macrophages, neuroinflammation

Introduction

The article published in the Journal of Cerebral Blood Flow and Metabolism entitled ‘Role of spleen-derived monocytes/macrophages in acute ischemic brain injury' written by Eunhee Kim et al1 2014 aims to establish the effect of experimental stroke on the spleen, specifically monocytes and macrophages (MMs), and in turn the consequential effect of those MMs on neurodegeneration. The article supports the previous reports2, 3, 4 that experimental stroke leads to splenic atrophy and spleen-derived, pro-inflammatory MM mobilization into the circulation and subsequent accumulation in the ischemic brain. This decrease in splenic size is inversely correlated with the extent of the infarct volume.5 The article goes on to claim that although splenectomy significantly reduces pro-inflammatory MMs in the ischemic brain, it does not affect infarct volume in their whole hemisphere assessment; therefore, spleen-derived monocytes have minimal involvement in acute infarct development. Conversely, multiple groups (including our unpublished data) have showed that pro-inflammatory macrophages contribute to neurodegeneration and that splenectomy 2 weeks before stroke is neuroprotective.6, 7, 8 The authors state that the lack of neuroprotection with splenectomy can be attributed to the time splenectomy was performed, immediately before middle cerebral artery occlusion (MCAO) in their case, which does not allow the body time to adapt or equilibrate to the loss of the spleen and to allow turnover of circulating splenocytes. However, Ostrowski et al9 showed that nonsurgical irradiation of the spleen immediately after experimental stroke reduces infarct by abrogating deployment of spleen cells to the brain. It is our opinion that by not allowing time for the immune system to get back to a resting state, splenectomy immediate before MCAO initiated an activation of the immune response, leading to tissue damage that canceled its protective effects in the brain.

There is a lot of variability with only 30 minutes of MCAO in the mouse and infarct may not always be detectable with 2,1,5-triphenyltetrazolium chloride stain. As shown in Figure 7 in the article by Kim et al1, there is considerable variability in infarct size (they present total or hemispheric infarct volume) in both groups. Regional infarct volume (cortex and striatum) was not separated from the total, which can uncover differences in these brain areas not detected using hemispheric measurements.

As stated above, removal of the spleen either surgically8, 10 or by radiation significantly reduces infarct volume9 after MCAO, suggesting that the elimination of splenocytes by any means may result in protection from ischemic injury. Splenectomy has also proven to be beneficial in other types of brain injuries, such as hemorrhagic stroke and traumatic brain injury.11, 12, 13, 14 In fact, the splenic response to ischemic injury occurs in organs throughout the body. Researchers in the field of liver injury were among the first to report that removal of the spleen before ischemia reperfusion injury to liver is hepatoprotective.15 Macrophages of the liver, Kupffer cells, and infiltrating neutrophils produce reactive oxygen species, tumor necrosis factor-alpha, and nitric oxide16 in response to ischemia reperfusion, which results in damage not only to the liver but also to kidney, heart, lungs, and intestine.17 Removal of the spleen reduces leukocyte infiltration and tumor necrosis factor-alpha release in liver tissue exposed to ischemia, thus protecting this tissue.18 Splenectomy also protects against damage from intestinal ischemia reperfusion and its subsequent inflammation that would induce cellular degeneration in other organs.19 Reports concerning other organ systems indicate that the removal of a spleen protects the kidney18 and the heart20 from ischemic injury by inhibition of the immune response to ischemic injury.

Conclusion

This splenic response to ischemic injury is similar in all other tissues and organ systems indicating that this is a general physiologic response to ischemia. Thus, our opinion is supported by these numerous studies that show the efficacy of the removal of the spleen in reducing infarct volume after MCAO.

Acknowledgments

Supported by RO1NS076013-03 to HO and R21NS078517-01 to KRP.

The authors declare no conflict of interest.

References

  1. 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;34:1411–1419. doi: 10.1038/jcbfm.2014.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26:654–665. doi: 10.1038/sj.jcbfm.9600217. [DOI] [PubMed] [Google Scholar]
  3. Offner H, Subramanian S, Parker SM, Wang C, Afentoulis ME, Lewis A, et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006;176:6523–6531. doi: 10.4049/jimmunol.176.11.6523. [DOI] [PubMed] [Google Scholar]
  4. Seifert HA, Leonardo CC, Hall AA, Rowe DD, Collier LA, Benkovic SA, et al. The spleen contributes to stroke induced neurodegeneration through interferon gamma signaling. Metab Brain Dis. 2012;27:131–141. doi: 10.1007/s11011-012-9283-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Vendrame M, Gemma C, Pennypacker KR, Bickford PC, Davis Sanberg C, Sanberg PR, et al. Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol. 2006;199:191–200. doi: 10.1016/j.expneurol.2006.03.017. [DOI] [PubMed] [Google Scholar]
  6. 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;126:2354–2360. [PubMed] [Google Scholar]
  7. Chiba T, Umegaki K. Pivotal roles of monocytes/macrophages in stroke. Mediat Inflamm. 2013;2013:759103. doi: 10.1155/2013/759103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ajmo CT, Jr., Vernon DO, Collier L, Hall AA, Garbuzova-Davis S, Willing A, et al. The spleen contributes to stroke-induced neurodegeneration. J Neurosci Res. 2008;86:2227–2234. doi: 10.1002/jnr.21661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ostrowski R, Schulte R, Nie Y, Ling T, Lee T, Manaenko A, et al. Acute splenic irradiation reduces brain injury in the rat focal ischemic stroke model. Transl Stroke Res. 2012;3:473–481. doi: 10.1007/s12975-012-0206-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jin R, Zhu X, Liu L, Nanda A, Granger DN, Li G. Simvastatin attenuates stroke-induced splenic atrophy and lung susceptibility to spontaneous bacterial infection in mice. Stroke. 2013;44:1135–1143. doi: 10.1161/STROKEAHA.111.000633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, et al. Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain. 2008;131:616–629. doi: 10.1093/brain/awm306. [DOI] [PubMed] [Google Scholar]
  12. Li M, Li F, Luo C, Shan Y, Zhang L, Qian Z, et al. Immediate splenectomy decreases mortality and improves cognitive function of rats after severe traumatic brain injury. J Trauma. 2011;71:141–147. doi: 10.1097/TA.0b013e3181f30fc9. [DOI] [PubMed] [Google Scholar]
  13. Das M, Leonardo CC, Rangooni S, Mohapatra SS, Mohapatra S, Pennypacker KR. Lateral fluid percussion injury of the brain induces CCL20 inflammatory chemokine expression in rats. J Neuroinflammation. 2011;8:148. doi: 10.1186/1742-2094-8-148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Walker PA, Shah SK, Jimenez F, Gerber MH, Xue H, Cutrone R, 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;225:341–352. doi: 10.1016/j.expneurol.2010.07.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Okuaki Y, Miyazaki H, Zeniya M, Ishikawa T, Ohkawa Y, Tsuno S, et al. Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat. Liver. 1996;16:188–194. doi: 10.1111/j.1600-0676.1996.tb00726.x. [DOI] [PubMed] [Google Scholar]
  16. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury. J Gastroenterol Hepatol. 2000;15:718–724. doi: 10.1046/j.1440-1746.2000.02207.x. [DOI] [PubMed] [Google Scholar]
  17. Fan C, Zwacka RM, Engelhardt JF. Therapeutic approaches for ischemia/reperfusion injury in the liver. J Mol Med. 1999;77:577–592. doi: 10.1007/s001099900029. [DOI] [PubMed] [Google Scholar]
  18. Jiang H, Meng F, Li W, Tong L, Qiao H, Sun X. Splenectomy ameliorates acute multiple organ damage induced by liver warm ischemia reperfusion in rats. Surgery. 2007;141:32–40. doi: 10.1016/j.surg.2006.03.024. [DOI] [PubMed] [Google Scholar]
  19. Savas MC, Ozguner M, Ozguner IF, Delibas N. Splenectomy attenuates intestinal ischemia-reperfusion-induced acute lung injury. J Pediatr Surg. 2003;38:1465–1470. doi: 10.1016/s0022-3468(03)00497-4. [DOI] [PubMed] [Google Scholar]
  20. Leuschner F, Panizzi P, Chico-Calero I, Lee WW, Ueno T, Cortez-Retamozo V, et al. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ Res. 2010;107:1364–1373. doi: 10.1161/CIRCRESAHA.110.227454. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Cerebral Blood Flow & Metabolism are provided here courtesy of SAGE Publications

RESOURCES