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Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway.

ABSTRACT:

Background

Skin wound healing is a challenging problem, especially in aging or diabetic patients, which becomes more difficult to heal, and easily results in considerable public health burden. The purpose of this study was to investigate the effects of metformin on wound healing and explore its underlying mechanism.

Methods

Metformin was local topical application in rat skin defect models. Alterations in the wounded skin were observed, and angiogenesis in the wound also was analyzed by immunohistochemical staining. The markers associated with differentiation macrophage were analyzed by immunofluorescence staining. The roles of AMPK singling pathway and the relative protein of NLRP3 inflammasome in wound were also analyzed by western blotting. In addition, AMPK/mTOR/NLRP3 inflammasome signaling axis was investigated to further analyze the molecular mechanism of metformin treatment on inducing M2 macrophage polarization in vitro.

Results

Out results showed that metformin improved wound healing and angiogenesis which was paralleled by M2 macrophage polarization. We also found that the level of relative proteins of NLRP3 inflammasome was markedly decreased after metformin treatment. Furthermore, blockage of AMPK or activation of mTOR abolished the effects of metformin treatment on depressing NLRP3 inflammasome activation, M2 polarization and improving wound healing. It suggested that the treatment effects of metformin on wound healing were through regulating AMPK/mTOR/NLRP3 inflammasome signaling axis.

Conclusion

Metformin regulated AMPK/mTOR singling pathway to inhibit NLRP3 inflammasome activation, which boosted M2 macrophage polarization to accelerate the wound healing. These findings provided new insights into the molecular mechanism of metformin therapy and its therapeutic potential in wound healing.

SUBMITTER: Qing L

PROVIDER: S-EPMC6413292 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:The aim of this study was to evaluate the therapeutic effects of Bletilla striata polysaccharide (BSP) on wound healing in diabetes mellitus (DM) and to explore the underlying mechanisms. DM mouse models were induced by high fat-diet feeding combined with low-dose streptozocin injection. To establish diabetic foot ulcer (DFU) models, DM mice were wounded on the dorsal surface. Subsequently, mice were treated with vehicle or BSP for 12 days and wound healing was monitored. The effects of BSP on the production of interleukin-1β (IL-1β), tumor necrosis factor-α, macrophages infiltration, angiogenesis, the activation of nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome, and insulin sensitivity in wound tissues were subsequently evaluated. Separated- and cultured- bone marrow-derived macrophages (BMDMs) and cardiac microvascular endothelial cells (CMECs) were isolated from mice and used to investigate the effects of BSP on cell viability, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation and insulin sensitivity in vitro following exposure to high glucose (HG). BSP administration accelerated diabetic wound healing, suppressed macrophage infiltration, promoted angiogenesis, suppressed NLRP3 inflammasome activation, decreased IL-1β secretion, and improved insulin sensitivity in wound tissues in DM mice. In vitro, co-treatment with BSP protected against HG-induced ROS generation, NLRP3 inflammasome activation, and IL-1β secretion in BMDMs, and improved cell viability and decreased ROS levels in CMECs. Moreover, in HG exposed BMDMs-CMECs cultures, BSP treatment suppressed NLRP3 inflammasome activation and IL-1β secretion in BMDMs, and improved cell viability and insulin sensitivity in CMECs. Furthermore, treatment with IL-1β almost completely suppressed the beneficial effects of BSP on the NLRP3 inflammasome, IL-1β secretion, and insulin sensitivity in HG-treated BMDMs-CMECs. BSP promotes DFU healing through inhibition of the HG-activated NLRP3 inflammasome.