Acetylation State of Histone Core Defines Macrophage Dynamics in Diabetic Wounds
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ABSTRACT:
PROVIDER: PRJNA762540 | ENA |
REPOSITORIES: ENA
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Project description:Dysregulation of macrophage populations at the wound site is responsible for the non-healing state of chronic wounds. The molecular mechanisms underlying macrophage dysfunction and its control in diabetes are largely unexplored on an epigenetic level. Here, we report that acetyl histone-H3 (Lys27), an epigenetic mark regulating the macrophage transcriptome, is lost in the hostile tissue microenvironment in diabetes. The diabetic microenvironment, profoundly suppresses the acetylation of histone by activating HDACs-dependent deacetylation pathways. This, in consequence, suppress the STAT1 signaling in macrophages maintained in diabetic conditions. Interestingly, the HDAC inhibitor butyrate - via restoring the acetyl histone-H3 (Lys27)-dependent transcriptome - effectively rescues macrophage functions in a diabetic microenvironment. Butyrate reinstalls the STAT1 mediated transcription program and consequently macrophage activity depicting a unique fingerprint of tissue regeneration and inflammation control even in a hostile diabetic microenvironment. Most interesting, butyrate breaks the vicious cycle of inflammation in diabetic wounds. Our study offers novel pathogenic insight and the unique opportunity to reverse perturbed macrophage function thus holding promise to successfully treat diabetic and other chronic wounds and conditions of unrestrained inflammation.
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Project description:Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here we focused onAlcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds withA. faecalisaccelerated healing during early stages. We investigated the underlying mechanisms and found thatA. faecalistreatment promotes re-epithelialization of diabetic keratinocytes, a process which is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found thatA. faecalistreatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.
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Project description:Diabetic infectious wounds treatment is challenging due to insistent wound infections. Treating such complicated pathological diabetic infectious wounds needs to develop multifunctional materials and understand their mechanism. Here, we developed a novel material termed AgNCs-hydrogel, which is a multifunctional DNA hydrogel which dressing by integrating antibacterial silver nanoclusters. AgNCs-hydrogel was used for promoting the regeneration of diabetic infectious wounds in mouses because that it exhibited superior antibacterial activity, satisfactory biocompatibility, and effective ROS-scavenging property. Based on the skin proteomics, we explored the potential mechanism of AgNCs-hydrogel in treating mouse skin wounds. We found that AgNCs-hydrogel can accelerate proliferation and extracellular matrix (ECM) formation. In proteomic level, AgNCs-hydrogel can regulate some key proteins which mainly located in the extracellular exosome, involved in negative regulation of apoptotic process, performed ATP binding for accelerating diabetic infected wound closure. Therefore, this study provided a multifunctional material AgNCs-hydrogel and revealed its potential mechanisms in promoting the regeneration of diabetic infectious wounds.
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