MDL-800, the SIRT6 Activator, Suppresses Inflammation via the NF-κB Pathway and Promotes Angiogenesis to Accelerate Cutaneous Wound Healing in Mice

Abstract

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase belonging to the sirtuin family. It has been shown to participate in wound healing and some inflammation-related disorders. However, the effect of MDL-800, a highly efficient and selective SIRT6 activator, on wound healing and inflammation has not been reported. Therefore, this study investigated whether MDL-800 confers anti-inflammatory effects and promotes wound healing and uncovered the molecular mechanisms involved. This was achieved using mouse models of full-thickness wounds. Results showed that MDL-800 significantly downregulated inflammation by attenuating the release of inflammatory mediators and improved collagen deposition and neovascularization of wounds, thereby accelerating cutaneous wound healing. Furthermore, MDL-800 significantly downregulated expression levels of TNF-α and IL-6 in the dorsal skin tissue of mice via the NF-κB pathway. These results demonstrated that MDL-800 exerted anti-inflammatory and prohealing effects, indicating that the SIRT6/NF-κB/IκB signaling pathway may play an important role in wound healing.

The sirtuin family in health and disease

“… 55 One recent study verified that SIRT6 suppressed inflammatory responses and downregulated the expression of inflammatory factors interleukin (IL)-6 and TNF-α via the NF-κB pathway. 56 For example, both SIRT1 and SIRT6 inhibited TNF-α-induced inflammation of vascular adventitial fibroblasts through reactive oxygen species (ROS) and the protein kinase B (Akt) signaling pathway. 57 SIRT1 exerted anti-inflammatory effects against IL-1β-mediated pro-inflammatory stress through the Toll-like receptor 2 (TLR2)/SIRT1/NF-κB pathway.…”

SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing through smad6/IκB/p65 signaling pathway

“…Previous studies have provided insights into NF-κb/IκB signaling, which exerts significant influences on the system-wide oxidative stress response, macrophage polarization and inflammation [ 41 , 42 ]. It was reported that the NF-κB/IκB signaling pathway played an important role in wound healing [ 43 ]. Suppression of the NF-κB/p65 pathway in fibroblasts promoted skin wound repair [ 44 ].…”

Investigating Inflammatory Markers in Wound Healing: Understanding Implications and Identifying Artifacts

“…28 It operates through various signaling pathways, notably the NF-κB pathway. 26 The activation of this pathway by IL-6 leads to the suppression of pro-inflammatory cytokines such as TNF-α, thereby exerting anti-inflammatory effects that are beneficial for healing. This dual role of IL-6, as both a promoter of initial inflammatory response and a mediator of subsequent healing processes, underscores its complex and critical function in wound healing dynamics.…”

“…This dual role of IL-6, as both a promoter of initial inflammatory response and a mediator of subsequent healing processes, underscores its complex and critical function in wound healing dynamics. 26 Interleukin-17 (IL-17). IL-17 plays a significant role in skin tissue by stimulating immunological responses and inflammation.…”