CD73 alleviates GSDMD-mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling.
CD73 alleviates GSDMD-mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling.
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CD73 通过 PI3K/AKT/Foxo1 信号传导减轻脊髓损伤中 GSDMD 介导的小胶质细胞焦亡
DOI：
10.1002/ctm2.269
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发表时间：
2021-01
影响因子：
10.6
通讯作者：
Lyu F
中科院分区：
文献类型：
--
作者：
Xu S;Wang J;Zhong J;Shao M;Jiang J;Song J;Zhu W;Zhang F;Xu H;Xu G;Zhang Y;Ma X;Lyu F
神经炎症诱导的继发性损伤是脊髓损伤持续发展的重要原因。由气孔形成蛋白气真皮蛋白D （GSDMD）执行的炎性程序性细胞死亡热亡是神经炎症的重要步骤。然而，目前尚不清楚CD73这种被广泛接受的免疫抑制分子是否可以通过介导GSDMD来抑制焦亡。本研究分别以C57BL/6J CD73缺陷小鼠和野生型小鼠、脂多糖（LPS）诱导的原代小胶质细胞和BV2细胞为实验对象，在体内和体外研究了CD73对小胶质细胞热凋亡的影响。采用分子和组织学相结合的方法对大鼠的焦亡进行了评价，并探讨了体内和体外的机制。我们已经证明CD73抑制NLRP3炎性体复合物的激活，以减少GSDMD的成熟，导致小胶质细胞焦亡减少。进一步分析表明，腺苷- A2B -腺苷受体- PI3K - AKT - Foxo1级联可能是CD73调控的机制之一。重要的是，我们确定CD73在转录水平上通过Foxo1抑制GSDMD的表达。此外，我们证实了HIF‐1α的积累促进了脊髓损伤后CD73的过表达，而CD73的增加反过来又上调了HIF‐1α的表达，最终形成了一个正反馈的调节回路。我们的数据揭示了CD73在小胶质细胞焦亡中的一种新功能，这为缓解脊髓损伤的疾病进程提供了独特的治疗机会。由气孔形成蛋白气真皮蛋白D （GSDMD）引起的炎性程序性细胞死亡焦亡是脊髓损伤后神经炎症的重要步骤。我们证明了CD73是一种被广泛接受的免疫抑制分子，可以通过PI3K/AKT/Foxo1信号介导GSDMD来抑制焦亡。
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‐A2B 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. Inflammatory programmed cell death pyroptosis executed by the pore‐forming protein gasdermin D (GSDMD) is an essential step of neuroinflammation after spinal cord injury. We demonstrated that CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD through PI3K/AKT/Foxo1 signaling.
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影响因子：
13.6
作者：
Antonioli L;Pacher P;Vizi ES;Haskó G
通讯作者：
Haskó G
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.
影响因子：
6.3
作者：
Adamczak, Stephanie E.;Vaccari, Juan Pablo de Rivero;Keane, Robert W.
通讯作者：
Keane, Robert W.
影响因子：
9.3
作者：
Liu W;Chen Y;Meng J;Wu M;Bi F;Chang C;Li H;Zhang L
通讯作者：
Zhang L
影响因子：
25
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Moore, Craig S.;Cialic, Ron;Lanser, Amanda J.;Gabriely, Galina;Koeglsperger, Thomas;Dake, Ben;Wu, Pauline M.;Doykan, Camille E.;Fanek, Zain;Liu, LiPing;Chen, Zhuoxun;Rothstein, Jeffrey D.;Ransohoffl, Richard M.;Gygi, Steven P.;Antel, Jack P.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.