CD73 alleviates GSDMD-mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling

Clin. Transl. Med., 2021 · DOI: 10.1002/ctm2.269 · Published: December 29, 2020

Simple Explanation

Inflammatory programmed cell death pyroptosis executed by the pore-forming protein gasdermin D (GSDMD) is an essential step of neuroinflammation after spinal cord injury. The study demonstrated that CD73, a widely accepted immunosuppressive molecule, can inhibit pyroptosis via mediating GSDMD through PI3K/AKT/Foxo1 signaling. The data reveal a novel function of CD73 on microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI.

Study Duration

Not specified

Participants

20 SCI patients and 20 healthy donors

Evidence Level

Not specified

Key Findings

1
CD73 suppresses the activation of NLRP3 inflammasome complexes to reduce the maturation of GSDMD, leading to decreased pyroptosis in microglia.
2
Adenosine-A2B adenosine receptor-PI3K-AKT-Foxo1 cascade is a possible mechanism of CD73 regulation.
3
CD73 inhibits the expression of GSDMD at the transcriptional level through Foxo1.

Research Summary

This study investigates the role of CD73 in alleviating GSDMD-mediated microglia pyroptosis in spinal cord injury (SCI) through the PI3K/AKT/Foxo1 signaling pathway. The research demonstrates that CD73 suppresses NLRP3 inflammasome activation, reduces GSDMD maturation, and decreases pyroptosis in microglia, mediated by the adenosine-A2B adenosine receptor-PI3K-AKT-Foxo1 cascade. The findings suggest that CD73 could be a potential therapeutic target for mitigating SCI by regulating microglia pyroptosis and reducing neuroinflammation.

Practical Implications

Therapeutic Target

CD73 may be a target molecule for the development of novel therapeutic methods for SCI.

Neuroinflammation Reduction

Targeting CD73 could reduce neuroinflammation after SCI.

Positive Feedback Loop

The creation of a positive feedback loop between CD73 and HIF-1α may be an important mechanism for reducing neuroinflammation after SCI.

Study Limitations

1
The alternative of BV2 cell line as primary microglia.
2
Didn’t confirm the correlation between NLRP3 inflammasome and pyroptosis in microglia.
3
The role of Caspase 11 in pyroptosis after SCI is still worthy of further study.

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