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Metformin Inhibited GSDME to Suppress M2 Macrophage Pyroptosis and Maintain M2 Phenotype to Mitigate
Ke Jiang1,2, Qi He2, Chenhui Wang2
1College of Pharmaceutical Sciences, Hebei University, Baoding 071002, China.
Background:
The continuous clinical use of cisplatin is prevented by gastrointestinal toxicity.
Methods:
Cisplatin was used to treat THP-1-derived macrophages to see its differential effects on different subtypes of macrophages. Wild-type and Gsdme-/- mice models were used to examine the effect of cisplatin and metformin on intestinal inflammation in vivo. The effect of GSDME on macrophage polarization was further confirmed by GSDME knockdown.
Results:
We found that M2 macrophages, with more cell blebbing and GSDME cleavage, were more sensitive to cisplatin-induced pyroptosis than M1 macrophages. Cisplatin was capable of enhancing the M1 phenotype, which was reversed by GSDME knockdown. GSDME contributed to M1 polarization and GSDME knockdown promoted M2 phenotype via STAT6 activation. Reduced intestinal inflammation and increased M2 macrophage numbers was detected in cisplatin-treated GSDME-knockout mice. Furthermore, metformin alleviated cisplatin-induced intestinal inflammation by reducing M2 pyroptosis and enhancing M2 phenotype through GSDME inhibition.
Conclusion:
This is the first study to reveal the non-pyroptotic role of GSDME in macrophage polarization, revealing that metformin could be used in combination with cisplatin to reduce intestinal toxicity.
Insights
Cisplatin causes gastrointestinal toxicity, but metformin can reduce this by inhibiting Gasdermin E (GSDME) and modulating macrophage polarization. This combination therapy shows promise for reducing chemotherapy side effects.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Cisplatin is a vital chemotherapy agent, but its clinical use is limited by severe gastrointestinal toxicity.
- Understanding the mechanisms underlying cisplatin-induced toxicity is crucial for developing supportive therapies.
Purpose of the Study:
- To investigate the differential effects of cisplatin on macrophage subtypes (M1 and M2).
- To elucidate the role of Gasdermin E (GSDME) in cisplatin-induced pyroptosis and macrophage polarization.
- To evaluate the potential of metformin in mitigating cisplatin-induced intestinal inflammation.
Main Methods:
- Differential effects of cisplatin on THP-1-derived macrophages were assessed.
- In vivo studies utilized wild-type and Gsdme knockout mice to examine intestinal inflammation.
- GSDME knockdown was employed to confirm its role in macrophage polarization.
Main Results:
- M2 macrophages exhibited higher sensitivity to cisplatin-induced pyroptosis than M1 macrophages due to increased GSDME cleavage.
- Cisplatin promoted M1 polarization, a process reversed by GSDME knockdown, which in turn promoted M2 polarization via STAT6.
- Metformin alleviated cisplatin-induced intestinal inflammation by inhibiting GSDME, reducing M2 pyroptosis, and enhancing M2 polarization.
Conclusions:
- This study reveals a non-pyroptotic function of GSDME in regulating macrophage polarization.
- Metformin demonstrates potential as an adjunct therapy with cisplatin to mitigate gastrointestinal toxicity.
