RESUMEN
AIMS: Remote ischemic preconditioning (RIPC) of a limb is a clinically feasible strategy to protect against ischemia-reperfusion injury after stroke. However, the mechanism underlying RIPC remains elusive. METHODS: We generated a rat model of noninvasive RIPC by four repeated cycles of brief blood flow constriction (5 min) in the hindlimbs using a tourniquet. Blood was collected 1 h after preconditioning and 3 days after brain reperfusion. The impact of RIPC on immune cell and cytokine profiles prior to and after transient middle cerebral artery occlusion (MCAO) was assessed. RESULTS: Remote ischemic preconditioning protects against focal ischemia and preserves neurological functions 3 days after stroke. Flow cytometry analysis demonstrated that RIPC ameliorates the post-MCAO reduction of CD3(+)CD8(+) T cells and abolishes the reduction of CD3(+)/CD161a(+) NKT cells in the blood. In addition, RIPC robustly elevates the percentage of B cells in peripheral blood, thereby reversing the reduction in the B-cell population after stroke. RIPC also markedly elevates the percentage of CD43(+)/CD172a(+) noninflammatory resident monocytes, without any impact on the percentage of CD43(-)/CD172a(+) inflammatory monocytes. Finally, RIPC induces IL-6 expression and enhances the elevation of TNF-α after stroke. CONCLUSION: Our results reveal dramatic immune changes during RIPC-afforded neuroprotection against cerebral ischemia.
Asunto(s)
Precondicionamiento Isquémico/métodos , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/prevención & control , Animales , Encéfalo/inmunología , Encéfalo/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Miembro Posterior/irrigación sanguínea , Miembro Posterior/fisiopatología , Infarto de la Arteria Cerebral Media , Interleucina-6/metabolismo , Masculino , Monocitos/fisiología , Neuroinmunomodulación/fisiología , Distribución Aleatoria , Ratas Sprague-Dawley , Accidente Cerebrovascular/patología , Linfocitos T/fisiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In the past decade, the significant contribution of the spleen to ischemic brain damage has gained considerable attention in stroke research. As the largest natural reservoir of immune cells, the spleen establishes critical connections with the ischemic brain during the progression of stroke and mobilizes its cells to the site of injury. Multiple "alarm" signals released from the injured brain are essential for the initiation of brain-spleen communication. Spleen-derived cells, including neutrophils, lymphocytes, and monocytes/macrophages, are known to contribute significantly to ischemic brain damage. Understanding the dynamic splenic responses to stroke will not only provide insights into the evolvement of ischemic brain injury but will also identify potential targets for stroke treatment. Here, we review recent studies on the functions of the spleen in ischemic stroke. We have included a discussion of several therapeutic strategies that target splenic responses and reduce acute ischemic brain damage in preclinical studies. Future investigations on the effects of the spleen on long-term stroke recovery are highly warranted.