ADSCs-derived exosomes suppress macrophage ferroptosis via the SIRT1/NRF2 signaling axis to alleviate acute lung injury in sepsis

Abstract

Acute lung injury being one of the earliest and most severe complications during sepsis and macrophages play a key role in this process. To investigate the regulatory effects and potential mechanisms of adipose mesenchymal stem cell derived-exosomes (ADSC-exo) on macrophages and septic mice, ADSCs-exo was administrated to both LPS-induced macrophage and cecal ligation and puncture (CLP) induced sepsis mice. ADSCs-exo was confirmed to inhibit M1 polarization of macrophages and to reduce excessive inflammation. The use of ADSCs-exo in CLP mice and in LPS-induced macrophages relieved oxidative stress, cellular damage, and acute lung injury. During this process, ADSCs-exo increased the nuclear translocation of Nrf2, significantly upregulating the activation of the antioxidant pathway Nrf2/HO-1. Concurrently, they enhanced the expression of SIRT1 in macrophages. Further SIRT1 interference experiments demonstrated that ADSCs-exo mitigated macrophage inflammatory responses and LPS-induced ferroptosis by upregulating SIRT1. In the LPS-induced macrophage model, after SIRT1 was interfered with, ADSCs-exo failed to upregulate the Nrf2/HO-1 signaling pathway, leading to enhanced ferroptosis. Finally, in a CLP sepsis mouse model with myeloid-specific SIRT1 knockout, ADSCs-exo was observed to reduce lung tissue injury, oxidative stress damage, and ferroptosis. Still, these beneficial effects were reversed due to the myeloid-specific knockout of SIRT1, while co-administration of a ferroptosis inhibitor rescued this situation, alleviating lung injury and significantly reducing tissue levels of oxidative stress. In conclusion, this study elucidated a novel potential therapeutic mechanism wherein ADSCs-exo upregulates the levels of SIRT1 in macrophages through a non-delivery approach.

Keywords: Acute lung injury; Exosome; Ferroptosis; Nrf2; SIRT1; Sepsis.