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CD73 alleviates GSDMD-mediated microglia pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling
Shun Xu1,2, Jin Wang2, Junjie Zhong3,4,5,6
1Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
Our data reveal a novel function of CD73 on microglia pyroptosis, suggesting a unique therapeutic opportunity for mitigating the disease process in SCI.
Insights
CD73, an immunosuppressive molecule, inhibits microglia pyroptosis by suppressing gasdermin D (GSDMD) maturation. This finding offers a potential therapeutic strategy for spinal cord injury (SCI) by targeting neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Spinal cord injury (SCI) progression is often driven by secondary injury mechanisms, including neuroinflammation.
- Pyroptosis, a form of inflammatory programmed cell death mediated by gasdermin D (GSDMD), is a key component of neuroinflammation.
- The role of the immunosuppressive molecule CD73 in regulating pyroptosis, particularly via GSDMD, remains largely unexplored.
Purpose of the Study:
- To investigate the effect of CD73 on microglia pyroptosis in the context of spinal cord injury.
- To elucidate the molecular mechanisms by which CD73 modulates pyroptosis and GSDMD activation.
- To explore the potential of CD73 as a therapeutic target for SCI.
Main Methods:
- Utilized CD73 deficient and wild-type mice, along with LPS-induced primary microglia and BV2 cell lines for in vivo and in vitro studies.
- Employed a combination of molecular biology and histological techniques to assess pyroptosis and investigate underlying mechanisms.
- Analyzed the role of the adenosine-A2B receptor-PI3K-AKT-Foxo1 pathway and HIF-1α in CD73-mediated regulation.
Main Results:
- Demonstrated that CD73 suppresses NLRP3 inflammasome activation, reducing GSDMD maturation and subsequent pyroptosis in microglia.
- Identified the adenosine-A2B receptor-PI3K-AKT-Foxo1 cascade as a key pathway in CD73's regulatory mechanism.
- Confirmed that CD73 inhibits GSDMD expression transcriptionally via Foxo1 and established a positive feedback loop involving HIF-1α and CD73 in SCI.
Conclusions:
- Revealed a novel inhibitory function of CD73 on microglia pyroptosis, distinct from its known immunosuppressive roles.
- Highlighted the therapeutic potential of targeting CD73 to mitigate neuroinflammation and secondary injury in spinal cord injury.
- Established a new regulatory axis involving CD73, GSDMD, and HIF-1α in the context of SCI pathogenesis.
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