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Melatonin Engineering M2 Macrophage-Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy.

ABSTRACT: Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play a crucial role in inflammatory response. An appropriate and timely transition from proinflammatory (M1) to anti-inflammatory (M2) macrophages is indispensable for treating periodontitis. As M2 macrophage-derived exosomes (M2-exos) can actively target inflammatory sites and modulate immune microenvironments, M2-exos can effectively treat periodontitis. Excessive endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) are highly destructive pathological characteristics during inflammatory periodontal bone loss. Although melatonin has antioxidant and anti-inflammatory effects, studies focusing on melatonin ER stress modulation remain limited. This study fabricates engineered M2-exos loading with melatonin (Mel@M2-exos) for treating periodontitis. As a result, M2-exos drive an appropriate and timely macrophage reprogramming from M1 to M2 type, which resolves chronic inflammation and accelerated periodontal healing. Melatonin released from Mel@M2-exos rescues the osteogenic and cementogenic differentiation capacity in inflammatory human periodontal ligament cells (hPDLCs) by reducing excessive ER stress and UPR. Injectable gelatin methacryloyl (GelMA) hydrogels with sustained-release Mel@M2-exos accelerate periodontal bone regeneration in rats with ligation-induced periodontitis. Taken together, melatonin engineering M2 macrophage-derived exosomes are promising candidates for inflammatory periodontal tissue regeneration.

SUBMITTER: Cui Y

PROVIDER: S-EPMC10520618 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Melatonin Engineering M2 Macrophage-Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy.

Cui Ya Y Hong Shebin S Xia Yunhui Y Li Xiaojing X He Xiaoya X Hu Xiangying X Li Yaxin Y Wang Xudong X Lin Kaili K Mao Lixia L

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230714 27

Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play a crucial role in inflammatory response. An appropriate and timely transition from proinflammatory (M1) to anti-inflammatory (M2) macrophages is indispensable for treating periodontitis. As M2 macrophage-derived exosomes (M2-exos) can actively target inflammatory sites and modulate immune microenvironments, M2-exos can effectively t ...[more]

PMID: 37452425

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Project description:BackgroundAfter surgery, wound recovery in diabetic patients may be disrupted due to delayed inflammation, which can lead to undesired consequences, and there is currently a lack of effective measures to address this issue. Mesenchymal stem cell (MSC)-derived exosomes (Exo) have been proven to be appropriate candidates for diabetic wound healing through the anti-inflammatory effects. In this study, we investigated whether melatonin (MT)-pretreated MSCs-derived exosomes (MT-Exo) could exert superior effects on diabetic wound healing, and we attempted to elucidate the underlying mechanism.MethodsFor the evaluation of the anti-inflammatory effect of MT-Exo, in vitro and in vivo studies were performed. For in vitro research, we detected the secreted levels of inflammation-related factors, such as IL-1β, TNF-α and IL-10 via ELISA and the relative gene expression of the IL-1β, TNF-α, IL-10, Arg-1 and iNOS via qRT-PCR and investigated the expression of PTEN, AKT and p-AKT by Western blotting. For in vivo study, we established air pouch model and streptozotocin (STZ)-treated diabetic wound model, and evaluated the effect of MT-Exo by flow cytometry, optical imaging, H&E staining, Masson trichrome staining, immunohistochemical staining, immunofluorescence, and qRT-PCR (α-SMA, collagen I and III).ResultsMT-Exo significantly suppressed the pro-inflammatory factors IL-1β and TNF-α and reduced the relative gene expression of IL-1β, TNF-α and iNOS, while promoting the anti-inflammatory factor IL-10 along with increasing the relative expression of IL-10 and Arg-1, compared with that of the PBS, LPS and the Exo groups in vitro. This effect was mediated by the increased ratio of M2 polarization to M1 polarization through upregulating the expression of PTEN and inhibiting the phosphorylation of AKT. Similarly, MT-Exo significantly promoted the healing of diabetic wounds by inhibiting inflammation, thereby further facilitating angiogenesis and collagen synthesis in vivo.ConclusionsMT-Exo could promote diabetic wound healing by suppressing the inflammatory response, which was achieved by increasing the ratio of M2 polarization to M1 polarization through activating the PTEN/AKT signalling pathway, and the pretreatment of MT was proved to be a promising method for treating diabetic wound healing.

Dataset Information

Melatonin Engineering M2 Macrophage-Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy.

Publications

Melatonin Engineering M2 Macrophage-Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy.

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