Department of Anesthesiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Department of Radiology and Biomedical Imaging, University of Virginia, Charlottesville, VA, 22908, USA.
Theranostics. 2022 Mar 21;12(7):3024-3044. doi: 10.7150/thno.57218. eCollection 2022.
Splenocyte contribution to ischemic brain injury has been suggested. It is not known whether this effect is due to systemic action or direct influence in ischemic brain tissues. It is also not known how splenocytes migrate into the brain and worsen neurological outcome after brain ischemia. We determined the role of formyl peptide receptor 1 (FPR1), a receptor expressed in monocytes, in the migration of splenocytes into ischemic brain tissues and the contribution of these splenocytes to ischemic brain injury. Mice with or without knockout were subjected to transient focal brain ischemia. The migration of splenocytes was assessed under and conditions. cFLFLF, a FPR1 antagonist, inhibited splenocyte migration into the brain and neuroinflammation after ischemic stroke. cFLFLF improved neurological outcome assessed 24 hours or 28 days after stroke. cFLFLF did not alter blood-brain barrier permeability in the ischemic brain. mice had an attenuated peripheral monocyte and neutrophil infiltration into the brain, a reduced proinflammatory cytokine level and an improved neurological outcome compared with wild-type mice after brain ischemia. cFLFLF did not affect the proinflammatory cytokine levels in the spleen and brain of mice after ischemic stroke. These results suggest that FPR1 facilitates splenocyte migration into the brain and proinflammatory cytokine production to worsen neurological outcome after brain ischemia, indicating a direct effect of splenocytes on ischemic brain tissues. Our results support the notion that cFLFLF via blocking FPR1 signaling inhibits those pathological processes and is a potential agent for neuroprotection.
已经有人提出脾细胞会对脑缺血损伤产生作用。但目前尚不清楚这种作用是源于全身作用还是对缺血脑组织的直接影响，也不知道脾细胞如何迁移到脑内并在脑缺血后导致神经功能恶化。我们旨在确定表达于单核细胞的甲酰肽受体 1（FPR1）在脾细胞向缺血性脑组织迁移以及脾细胞对缺血性脑损伤的作用中的角色。在野生型或 FPR1 敲除型小鼠中进行短暂性局灶性脑缺血，在 和 条件下评估脾细胞的迁移。FPR1 拮抗剂 cFLFLF 抑制缺血性中风后脾细胞向脑内迁移和神经炎症。cFLFLF 可改善中风后 24 小时或 28 天的神经功能。cFLFLF 不改变缺血脑内的血脑屏障通透性。与野生型小鼠相比，脑缺血后 FPR1 敲除型小鼠的外周单核细胞和中性粒细胞向脑内浸润减少、促炎细胞因子水平降低以及神经功能改善。cFLFLF 不影响缺血性中风后 FPR1 敲除型小鼠的脾和脑内促炎细胞因子水平。这些结果表明，FPR1 促进脾细胞向脑内迁移和促炎细胞因子的产生，从而使脑缺血后的神经功能恶化，表明脾细胞对缺血性脑组织具有直接作用。我们的结果支持这样的观点，即 cFLFLF 通过阻断 FPR1 信号转导抑制这些病理过程，是一种有潜力的神经保护剂。
