Department of Biology, Texas A&M University, 301 Old Main Dr, ILSB 3128, College Station, TX, 77843, USA.
Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA.
J Neuroinflammation. 2021 Dec 24;18(1):302. doi: 10.1186/s12974-021-02353-2.
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 (SykMRP8-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.
脊髓损伤会引发广泛的炎症，从而加剧长期的神经功能缺损。中性粒细胞是损伤后早期急性阶段入侵脊髓的最丰富的免疫细胞类型，但其在继发性发病机制和功能恢复中的作用尚不清楚。我们之前的研究表明，在炎症过程中，中性粒细胞的功能反应会被脾酪氨酸激酶（Syk）增强，Syk 是一种重要的细胞内信号酶。在这项研究中，我们评估了 Syk 在脊髓损伤后中性粒细胞功能和长期神经功能缺损中的作用。
在小鼠第 9 胸椎水平进行挫伤性脊髓损伤，在中性粒细胞中条件性缺失 Syk（SykMRP8-Cre）。在脊髓损伤后 35 天，通过旷场测试评估后肢运动功能恢复情况。使用 Eriochrome Cyanide 染色评估长期白质保留情况。通过免疫印迹评估血脊髓屏障破坏情况。通过流式细胞术测定中性粒细胞浸润、激活、效应功能和细胞死亡情况。使用基因芯片评估中性粒细胞中细胞因子和趋化因子的表达情况。
中性粒细胞中 Syk 的缺失改善了脊髓损伤后的长期功能恢复，但并未促进长期白质保留。Syk 的遗传缺失减轻了急性损伤脊髓中中性粒细胞的激活、细胞因子表达和细胞死亡，但不影响中性粒细胞的浸润和效应功能。急性血脊髓屏障破坏也不受中性粒细胞中 Syk 缺失的影响。
Syk 促进了特定的中性粒细胞对脊髓损伤的反应，包括激活、细胞因子表达和细胞死亡。中性粒细胞中 Syk 信号的缺失加剧了长期神经功能缺损，而与急性血脊髓屏障破坏和长期白质保留无关。这些发现表明，Syk 参与了加重脊髓损伤后长期功能恢复的致病中性粒细胞活动。
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