Therapeutic potential of ADSC-derived exosomes in acute lung injury by regulating macrophage polarization through IRF7/NLRP3 signaling

Alveolar macrophages (AMs) play a critical role in regulating pulmonary immunity and inflammation. Acute lung injury (ALI), frequently initiated by sepsis-induced systemic inflammation and cytokine storms, leads to heightened lung permeability and respiratory failure. Adipose-derived stem cell exosomes (ADSC-Exos) have shown promise as therapeutic agents due to their immunomodulatory properties. This study assesses the effectiveness of ADSC-Exos in mitigating ALI by modulating macrophage (mø) polarization and suppressing pyroptosis. In vivo, an LPS-induced ALI mouse model demonstrated that ADSC-Exos attenuated lung tissue inflammation and damage, as verified by histological staining, ELISA, and immunofluorescence. In vitro, LPS-stimulated MH-S cells treated with ADSC-Exos showed a decrease in M1 (iNOS, CD86) and an increase in M2 (CD206, Arg-1) markers, as evidenced by Western blotting (WB) and flow cytometry. Mechanistically, RNA sequencing pinpointed IRF7 as a key upstream regulator of pyroptosis. ADSC-Exos inhibited the NLRP3 inflammasome and pyroptosis, fostering a shift from pro-inflammatory M1 to anti-inflammatory M2 mø phenotypes. Overexpression of IRF7 negated these effects, undermining the protective role of ADSC-Exos. Notably, inhibition of exosome secretion with GW4869 nullified these immunomodulatory effects, underscoring the vital role of ADSC-Exos. This study underscores the therapeutic potential of ADSC-Exos in restoring alveolar mø homeostasis, modulating immune responses, and alleviating lung inflammatory injury in ALI. These findings suggest ADSC-Exos as a feasible strategy for treating sepsis-induced pulmonary complications.