Disulfiram Improves Fat Graft Retention by Modulating Macrophage Polarization With Inhibition of NLRP3 Inflammasome-Mediated Pyroptosis

Background: Macrophage-mediated inflammatory response in the early post-grafting period restricts fat graft retention. Pyroptosis is a novel type of programmed cell death that extensively participates in inflammatory pathologies.

Objectives: This study sought to determine whether macrophage Pyroptosis was activated during the inflammatory phase after fat grafting and to investigate the efficacy of a Pyroptosis inhibitor, disulfiram (DSF), in fat graft retention.

Methods: We established a C57BL/6 mice fat grafting model and then analyzed macrophage Pyroptosis. DSF (50 mg/kg, every Other day) was intraperitoneally injected starting 1 hour before fat grafting and continued for 14 days. An in vitro co-culture system was established in which mouse RAW264.7 macrophages were co-cultured with apoptotic adipocytes to further validate the findings of the in vivo studies and to explore the underlying mechanisms.

Results: Here we reported that macrophage Pyroptosis was activated in both fat grafts and in vitro co-culture models. DSF was found to be a potent Pyroptosis inhibitor, promoting M2 macrophage polarization. In addition, DSF was demonstrated to enhance vascularization and graft retention.

Conclusions: Our results suggested that Pyroptosis plays a crucial role in the inflammatory cascade within fat grafts. DSF, being a clinically available drug, could be translated into a clinically effective drug for improving fat graft survival by inhibiting macrophage Pyroptosis, therefore inducing M2 macrophage polarization and promoting neovascularization.