The Role of the Spleen in Ischemic Stroke

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.

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 al ¹ 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 reports^{2, 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 Conversely, multiple groups (including our unpublished data) have showed that pro-inflammatory macrophages contribute to neurodegeneration and that splenectomy 2 weeks before stroke is neuroprotective.^{6, 7, 8}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 al ⁹ 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 al ¹ , 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 surgically^{8, 10} or by radiation significantly reduces infarct volume ⁹ 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 oxide ¹⁶ 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 kidney ¹⁸ and the heart ²⁰ 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.