Department of Child Healthcare, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
College of Life Sciences, Chongqing Normal University, Chongqing, People's Republic of China.
J Neurophysiol. 2024 Sep 1;132(3):722-732. doi: 10.1152/jn.00079.2024. Epub 2024 Jun 26.
Sensorimotor deficits following stroke remain a major cause of disability, but little is known about the specific pathological mechanisms. Exploring the pathological mechanisms and identifying potential therapeutic targets to promote functional rehabilitation after stroke are essential. CXCL10, also known as interferon-γ-inducible protein 10 (IP-10), plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke is still unclear. In this study, mice were subjected to photothrombotic (PT) stroke, and sensorimotor deficits were determined by the ladder walking tests, tape removal tests, and rotarod tests. The density of dendritic spines and synaptic plasticity was determined in Thy1-EGFP mice and evaluated by electrophysiology. We found that photothrombotic stroke induced sensorimotor deficits and upregulated the expression of CXCL10, whereas suppressing the expression of CXCL10 by adeno-associated virus (AAV) ameliorated sensorimotor deficits and increased the levels of synapse-related proteins, the density of dendritic spines, and synaptic strength. Furthermore, the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulus of interferon genes (STING) pathway was activated by stroke and induced CXCL10 release, and cGAS or STING antagonists downregulated the levels of CXCL10 and improved synaptic plasticity after stroke. Collectively, our results indicate that cGAS-STING pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery. Chemokine-mediated inflammatory response plays a critical role in stroke. CXCL10 plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke recovery is still unclear. Herein, we identified a new mechanism that cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulus of interferon genes (STING) pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery. Our findings highlight the potential therapeutic strategy of targeting the cGAS-STING pathway to treat stroke.
中风后的运动感觉障碍仍然是残疾的主要原因，但对于具体的病理机制知之甚少。探索病理机制并确定潜在的治疗靶点，以促进中风后的功能康复至关重要。趋化因子 (C-X-C 基元) 配体 10(CXCL10)，也称为干扰素-γ诱导蛋白 10(IP-10)，通过调节突触可塑性在多种脑部疾病中发挥重要作用，但在中风中的作用尚不清楚。在这项研究中，使用光血栓形成(PT)中风模型诱导小鼠中风，使用梯级行走测试、胶带去除测试和转棒测试来确定运动感觉缺陷。在 Thy1-EGFP 小鼠中确定树突棘密度和突触可塑性，并通过电生理学进行评估。我们发现光血栓形成中风诱导运动感觉缺陷，并上调 CXCL10 的表达，而通过腺相关病毒(AAV)抑制 CXCL10 的表达可改善运动感觉缺陷，并增加突触相关蛋白、树突棘密度和突触强度。此外，中风激活了环鸟苷酸-腺苷酸(cGAMP)合酶(cGAS)-干扰素基因刺激因子(STING)通路，诱导 CXCL10 释放，cGAS 或 STING 拮抗剂下调 CXCL10 水平并改善中风后的突触可塑性。总之，我们的结果表明，cGAS-STING 通路激活促进中风恢复过程中 CXCL10 的释放和突触可塑性受损。趋化因子介导的炎症反应在中风中起关键作用。趋化因子 (C-X-C 基元) 配体 10(CXCL10)，也称为干扰素-γ诱导蛋白 10(IP-10)，通过调节突触可塑性在多种脑部疾病中发挥重要作用，但在中风恢复中的作用尚不清楚。在此，我们确定了一种新的机制，即环鸟苷酸-腺苷酸(cGAMP)合酶(cGAS)-干扰素基因刺激因子(STING)通路激活促进 CXCL10 释放并损害中风恢复过程中的突触可塑性。我们的研究结果强调了靶向 cGAS-STING 通路治疗中风的潜在治疗策略。
