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Published on: November 6, 2020
Low-dose mycophenolate mofetil improves survival in a murine model of Staphylococcus aureus sepsis by increasing
Fanny Alby-Laurent1, Nadia Belaïdouni1, Benoit Blanchet2
1Cochin Institute, Department of Infection, Immunity and Inflammation, Inserm U1016, Paris Descartes Sorbonne Paris Cité University UMR-S1016, Centre National de la Recherche Scientifique (CNRS) UMR 8104, Paris, France.
Abstract:
Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressive doses has an impact on survival and on innate immune response in sepsis is unknown. C57BL/6J mice were infected intraperitoneally with 108 CFU Staphylococcus aureus, and treated or not with low-dose of MMF (20mg/kg/day during 4 days). Survival rate and bacterial clearance were compared. Cytokine levels, quantitative and qualitative cellular responses were assessed. S. aureus - infected mice treated with MMF exhibited improved survival compared to non-treated ones (48% vs 10%, p<0.001). With the dose used for all experiments, MMF did not show any effect on lymphocyte proliferation. MMF treatment also improved local and systemic bacterial clearance, improved phagocytosis activity of peritoneal macrophages resulting in decreased inflammatory cytokines secretion. MMF-treated mice showed enhanced activation of NF-κB seemed with a suspected TLR4-dependent mechanism. These results suggest that infra-immunosuppressive doses of MMF improve host defense during S. aureus sepsis and protects infected mice from fatal outcome by regulating innate immune responses. The signaling pathways involved could be TLR4-dependent. This work brings new perspectives in pathogenesis and therapeutic approaches of severe infections.
Insights
Low-dose Mycophenolate mofetil (MMF) significantly improved survival in Staphylococcus aureus sepsis by enhancing innate immune responses. MMF boosted bacterial clearance and macrophage activity without suppressing lymphocytes.
Area of Science:
- Immunology
- Infectious Diseases
- Pharmacology
Background:
- Toll-like receptor (TLR) signaling pathways are crucial in regulating inflammatory responses during sepsis.
- Mycophenolate mofetil (MMF), an immunosuppressant, is known to modulate TLR signaling.
- The effect of sub-immunosuppressive MMF doses on sepsis survival and innate immunity remains unexplored.
Purpose of the Study:
- To investigate the impact of infra-immunosuppressive doses of MMF on survival and innate immune responses in Staphylococcus aureus sepsis.
- To determine if MMF at low doses affects lymphocyte proliferation in sepsis models.
- To elucidate the mechanisms by which MMF might influence host defense during sepsis.
Main Methods:
- C57BL/6J mice were infected with Staphylococcus aureus and treated with low-dose MMF (20mg/kg/day for 4 days).
- Survival rates, bacterial clearance, cytokine levels, and cellular responses were assessed.
- Phagocytosis activity and NF-κB activation were analyzed to understand immune modulation.
Main Results:
- MMF treatment significantly improved survival rates in S. aureus-infected mice (48% vs 10%).
- Low-dose MMF enhanced bacterial clearance and macrophage phagocytic activity, reducing inflammatory cytokine secretion.
- MMF did not suppress lymphocyte proliferation at the tested dose and appeared to enhance NF-κB activation, potentially via TLR4.
Conclusions:
- Infra-immunosuppressive doses of MMF enhance host defense mechanisms against Staphylococcus aureus sepsis.
- MMF improves survival by modulating innate immune responses, including macrophage function and TLR4-dependent pathways.
- These findings suggest MMF as a potential therapeutic agent for severe infections, offering protection without significant immunosuppression.
