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Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages
Fang-Yi Yu1, Kua Zheng1, Yin-Fang Wu1
1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
Purpose:
This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism.
Methods:
We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models.
Results:
Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia.
Conclusion:
Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.
Insights
Rapamycin (Rapa) worsens Staphylococcus aureus (S. aureus) pneumonia by increasing inflammation in macrophages. Inhibiting the mTOR-RPS6 pathway boosts inflammatory responses, worsening S. aureus pneumonia outcomes.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- Staphylococcus aureus (S. aureus) is a common cause of bacterial pneumonia.
- Rapamycin (Rapa) is an immunosuppressant drug with potential immunomodulatory effects.
- The role of Rapa in S. aureus pneumonia requires further elucidation.
Purpose of the Study:
- To investigate the effect of Rapamycin (Rapa) on Staphylococcus aureus (S. aureus) pneumonia.
- To clarify the underlying mechanisms of Rapa's action in S. aureus pneumonia.
Main Methods:
- S. aureus pneumonia mouse models and in vitro macrophage cultures were used.
- Investigated mTOR-RPS6 pathway phosphorylation and phagocytosis.
- Utilized myeloid cell-specific Mtor knockout mice for in vivo validation.
Main Results:
- Rapa exacerbated S. aureus pneumonia, increasing chemokine secretion and inflammatory cell infiltration.
- In vitro, Rapa upregulated macrophage chemokine and cytokine secretion.
- mTOR-RPS6 pathway inhibition increased inflammation; Rapa did not enhance phagocytosis.
Conclusions:
- Rapamycin exacerbates S. aureus pneumonia by amplifying macrophage inflammatory responses.
- Inhibition of the mTOR-RPS6 pathway promotes inflammation, worsening S. aureus pneumonia severity and tissue damage.
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