Rapamycin Exacerbates Staphylococcus aureus Pneumonia by Inhibiting mTOR-RPS6 in Macrophages

Abstract

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.

Keywords:

• Staphylococcus aureus
• pneumonia
• macrophage
• rapamycin
• mTOR- ribosomal protein S6 signaling pathway

Data Sharing Statement

The data of this study are available from the corresponding author.

Ethics Approval and Informed Consent

This study was performed in line with the Ethical Committee for Animal Studies at Zhejiang University and followed the procedures and principles of the experimental animal welfare and ethical review of Zhejiang University for the care of laboratory animals.

Consent for Publication

This manuscript has never been published or accepted elsewhere. The manuscript is not currently under consideration for publication elsewhere. All authors of this paper have read and approved the publication of this manuscript.

Disclosure

The authors disclosed no relevant financial or non-financial interests in this work.

Additional information

Funding

This research was supported by the National Natural Science Foundation of China (U22A20265, 82270023 and 82100001) and the Zhejiang Provincial Natural Science Foundation of China (LQ22H010006, LD21H010001).