The spleen contributes to stroke‐induced neurodegeneration

Abstract

Stroke, a cerebrovascular injury, is the leading cause of disability and third leading cause of death in the world. Recent reports indicate that inhibiting the inflammatory response to stroke enhances neurosurvival and limits expansion of the infarction. The immune response that is initiated in the spleen has been linked to the systemic inflammatory response to stroke, contributing to neurodegeneration. Here we show that removal of the spleen significantly reduces neurodegeneration after ischemic insult. Rats splenectomized 2 weeks before permanent middle cerebral artery occlusion had a >80% decrease in infarction volume in the brain compared with those rats that were subjected to the stroke surgery alone. Splenectomy also resulted in decreased numbers of activated microglia, macrophages, and neutrophils present in the brain tissue. Our results demonstrate that the peripheral immune response as mediated by the spleen is a major contributor to the inflammation that enhances neurodegeneration after stroke.

The Role of the Spleen in Ischemic Stroke

“…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.…”

“…Conversely, multiple groups (including our unpublished data) have showed that proinflammatory macrophages contribute to neurodegeneration and that splenectomy 2 weeks before stroke is neuroprotective.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.…”

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Indeed, after over 20 years of innovative research, the events triggering motor neuron death in SMA remain elusive. It is interesting to note that lymphoid organs, and more specifically the spleen, may actively participate in the process of neurodegeneration 39. ALS, an adult onset motor neuron disorder, has received attention from the SMA community for their possible common molecular ties in disease pathogenesis 40.…”

Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery?

“…In parallel to events within the brain, lymphocytes, neutrophils, and monocytes traffic to the brain from the periphery and contribute to further neuronal damage. The spleen is a principal reservoir that reduces in size after stroke, releasing inflammatory cells and cytokines into the circulation [8][9][10][11][12][13][14][15]. In addition, the bone marrow mobilizes a subpopulation of multipotent stem cells into the peripheral blood following stroke, which is then directed towards the brain, as well as peripheral organs such as the spleen [16].…”

“…There are many studies establishing a role for the spleen in the inflammatory processes following ischemia-perfusion injury of various organs or trauma, with some even showing the importance of splenectomy in reducing the proinflammatory response [13,64,65]. As splenectomy is not feasible in patients with stroke, a novel method such as controlling poststroke inflammatory response by enhancing the CD25 bright subpopulation of regulatory T cells could prove useful [66].…”