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A Mouse Model of Vascularized Heterotopic Spleen Transplantation for Studying Spleen Cell Biology and Transplant Immunity
Published on: June 11, 2019
Splenic SUMO1 controls systemic inflammation in experimental sepsis
Ayman Youssef1, Bilal Khan Mohammed1, Abhishek Prasad1
1Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States.
Introduction:
The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting.
Methods:
We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis.
Results And Discussion:
Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia.
Conclusion:
These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.
Insights
TAK981, a SUMOylation inhibitor, improved survival in sepsis by boosting immune responses. Spleen SUMO1 regulation is key to modulating immune and metabolic responses during bacterial infections.
Area of Science:
- Immunology
- Molecular Biology
- Sepsis Research
Background:
- TAK981 (Subasumstat) is a novel SUMOylation inhibitor with potential in cancer immunotherapy.
- Cancer patients face increased infection risk, but TAK981's effects on sepsis are unknown.
- Previous research on SUMOylation in infections yielded conflicting results.
Purpose of the Study:
- To investigate the effects of TAK981 on immune responses and survival in experimental sepsis models.
- To elucidate the role of the spleen and SUMOylation (SUMO1 and SUMO3) in sepsis pathogenesis.
- To determine if TAK981 can modulate immune and metabolic responses during bacterial infection.
Main Methods:
- Utilized polymicrobial peritonitis (CLP) and LPS endotoxemia models in mice.
- Investigated the impact of splenectomy on sepsis outcomes and immune responses.
- Employed Western blotting to analyze SUMO-conjugated proteins in spleen lysates.
- Used global SUMO1 and SUMO3 knockout mice and splenocyte adoptive transfer to assess specific SUMO regulation.
Main Results:
- TAK981 enhanced survival in mild polymicrobial peritonitis by improving innate immunity and bacterial clearance.
- In LPS endotoxemia, TAK981 boosted early TNFα production but did not alter inflammation resolution.
- Splenectomy significantly reduced serum TNFα levels and TAK981-mediated responses.
- Endotoxemia showed specific SUMO1 and SUMO2/3 conjugation in the spleen, both inhibited by TAK981.
- SUMO1 deficiency, but not SUMO3, exacerbated TNFα production and metabolic acidosis in endotoxemia.
- Transfer of SUMO1-null splenocytes worsened endotoxemia outcomes in splenectomized mice.
Conclusions:
- TAK981 demonstrates potential therapeutic benefits in sepsis by modulating innate immune responses.
- Splenic SUMO1 plays a critical role in regulating immune and metabolic responses to bacterial infections.
- Targeting splenic SUMO1 may offer a novel strategy for managing sepsis.
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