Guilongwan Promoted Diabetic Wound Healing via Inhibition of TLR4/NLRP3 Signaling Pathway in Macrophages

Guilongwan (GLW), a modified formulation derived from the Danggui Sini decoction, is often clinically used to promote wound healing in patients with diabetes. This study further explored its therapeutic efficacy and underlying mechanisms both in vivo and in vitro. GLW treatment showed apparently improved diabetic wound healing and decreased the expression levels of pyroptosis-related markers of the wound tissues in diabetic rats. GLW inhibited the activation of the nuclear factor-kappa-B (NF-κB)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in diabetic wound tissues and targeting NLRP3 and hypoxia-inducible factor 1 alpha (HIF-1α) in the macrophages. Consistently, GLW-containing serum and its active ingredients, trans-ferulic acid and paeoniflorin, also suppressed HIF-1α and NLRP3 signalings in lipopolysaccharide (LPS)- and adenosine triphosphate (ATP)-induced pyroptotic macrophages in vitro. Furthermore, trans-ferulic acid and paeoniflorin might directly interact with toll-like receptor 4 (TLR4). In conclusion, this study demonstrated that GLW significantly improved wound healing in diabetic rats by suppressing TLR4/NLRP3-mediated pyroptosis in macrophages. The findings provided a therapeutic basis of GLW for the clinical application on diabetic wounds.