Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, China.
Clin Transl Med. 2021 Jan;11(1):e269. doi: 10.1002/ctm2.269.
Neuroinflammation-induced secondary injury is an important cause of sustained progression of spinal cord injury. Inflammatory programmed cell death pyroptosis executed by the pore-forming protein gasdermin D (GSDMD) is an essential step of neuroinflammation. However, it is unclear whether CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD.
C57BL/6J CD73 deficient mice and wild-type mice, Lipopolysaccharide (LPS)-induced primary microglia and BV2 cells were respectively used to illustrate the effect of CD73 on microglia pyroptosis in vivo and in vitro. A combination of molecular and histological methods was performed to assess pyroptosis and explore the mechanism both in vivo and in vitro.
We have shown molecular evidence for CD73 suppresses the activation of NLRP3 inflammasome complexes to reduce the maturation of GSDMD, leading to decreased pyroptosis in microglia. Further analysis reveals that adenosine-A adenosine receptor-PI3K-AKT-Foxo1 cascade is a possible mechanism of CD73 regulation. Importantly, we determine that CD73 inhibits the expression of GSDMD at the transcriptional level through Foxo1. What's more, we confirm the accumulation of HIF-1α promotes the overexpression of CD73 after spinal cord injury (SCI), and the increased CD73 in turn upregulates the expression of HIF-1α, eventually forming a positive feedback regulatory loop.
Our data reveal a novel function of CD73 on microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI.
神经炎症诱导的继发性损伤是脊髓损伤持续进展的重要原因。炎性程序性细胞死亡细胞焦亡由孔形成蛋白 GSDMD（gasdermin D）执行，是神经炎症的关键步骤。然而，CD73（一种广泛认可的免疫抑制分子）是否可以通过介导 GSDMD 来抑制细胞焦亡尚不清楚。
使用 C57BL/6J CD73 缺陷型小鼠和野生型小鼠、脂多糖（LPS）诱导的原代小胶质细胞和 BV2 细胞，分别在体内和体外阐明 CD73 对小胶质细胞细胞焦亡的影响。采用分子和组织学方法评估体内和体外的细胞焦亡，并探讨其机制。
我们提供了分子证据表明，CD73 抑制 NLRP3 炎性小体复合物的激活，从而减少 GSDMD 的成熟，导致小胶质细胞细胞焦亡减少。进一步分析表明，腺苷 A 受体-PI3K-AKT-Foxo1 级联是 CD73 调节的可能机制。重要的是，我们确定 Foxo1 通过转录水平抑制 GSDMD 的表达。此外，我们证实了脊髓损伤（SCI）后 HIF-1α 的积累促进了 CD73 的过度表达，而增加的 CD73 又反过来上调了 HIF-1α 的表达，最终形成一个正反馈调节环。
我们的数据揭示了 CD73 对小胶质细胞细胞焦亡的新功能，为减轻 SCI 疾病进程提供了独特的治疗机会。
