Spleen tyrosine kinase facilitates neutrophil activation and worsens long-term neurologic deficits after spinal cord injury.
Spleen tyrosine kinase facilitates neutrophil activation and worsens long-term neurologic deficits after spinal cord injury.
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DOI：
10.1186/s12974-021-02353-2
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发表时间：
2021-12-24
影响因子：
9.3
通讯作者：
Lowell CA
中科院分区：
文献类型：
--
作者：
McCreedy DA;Abram CL;Hu Y;Min SW;Platt ME;Kirchhoff MA;Reid SK;Jalufka FL;Lowell CA
脊髓损伤引起广泛的炎症，可加重长期的神经功能缺损。中性粒细胞是在损伤后早期急性期侵入脊髓的最丰富的免疫细胞类型，然而，它们在继发性发病机制和功能恢复中的作用仍不清楚。我们以前已经表明，中性粒细胞的功能反应在炎症过程中增强脾酪氨酸激酶，Syk，一个突出的细胞内信号传导酶。在这项研究中，我们评估了Syk对中性粒细胞功能和脊髓损伤后长期神经功能缺损的贡献。在中性粒细胞中条件性缺失Syk（Sykf/fMRP 8-Cre）的小鼠中在胸椎9级进行挫伤性脊髓损伤。脊髓损伤后35天，采用旷场试验评价后肢运动恢复。长期白色物质保留使用铬氰化物染色进行评估。通过免疫印迹法评价血脊髓屏障破坏。通过流式细胞术测定神经元浸润、活化、效应子功能和细胞死亡。使用基因阵列评估中性粒细胞中的细胞因子和趋化因子表达。中性粒细胞中Syk的缺乏可以改善脊髓损伤后的长期功能恢复，但并不能促进长期的白色物质保留。Syk基因缺失可减弱急性损伤脊髓中的中性粒细胞活化、细胞因子表达和细胞死亡，而中性粒细胞浸润和效应子功能不受影响。急性血-脊髓屏障破坏也不受中性粒细胞Syk缺乏的影响。Syk促进对脊髓损伤的特异性中性粒细胞功能反应，包括活化、细胞因子表达和细胞死亡。中性粒细胞中Syk信号转导可加重长期神经功能缺损，与急性血-脊髓屏障破坏和长期白色物质保留无关。这些发现暗示Syk参与了致病性中性粒细胞活动，使脊髓损伤后的长期功能恢复恶化。
Spinal cord injury elicits widespread inflammation that can exacerbate long-term neurologic deficits. Neutrophils are the most abundant immune cell type to invade the spinal cord in the early acute phase after injury, however, their role in secondary pathogenesis and functional recovery remains unclear. We have previously shown that neutrophil functional responses during inflammation are augmented by spleen tyrosine kinase, Syk, a prominent intracellular signaling enzyme. In this study, we evaluated the contribution of Syk towards neutrophil function and long-term neurologic deficits after spinal cord injury. Contusive spinal cord injury was performed at thoracic vertebra level 9 in mice with conditional deletion of Syk in neutrophils (Sykf/fMRP8-Cre). Hindlimb locomotor recovery was evaluated using an open-field test for 35 days following spinal cord injury. Long-term white matter sparing was assessed using eriochrome cyanide staining. Blood-spinal cord barrier disruption was evaluated by immunoblotting. Neutrophil infiltration, activation, effector functions, and cell death were determined by flow cytometry. Cytokine and chemokine expression in neutrophils was assessed using a gene array. Syk deficiency in neutrophils improved long-term functional recovery after spinal cord injury, but did not promote long-term white matter sparing. Neutrophil activation, cytokine expression, and cell death in the acutely injured spinal cord were attenuated by the genetic loss of Syk while neutrophil infiltration and effector functions were not affected. Acute blood-spinal cord barrier disruption was also unaffected by Syk deficiency in neutrophils. Syk facilitates specific neutrophil functional responses to spinal cord injury including activation, cytokine expression, and cell death. Long-term neurologic deficits are exacerbated by Syk signaling in neutrophils independent of acute blood-spinal cord barrier disruption and long-term white matter sparing. These findings implicate Syk in pathogenic neutrophil activities that worsen long-term functional recovery after spinal cord injury.