ArticleCell communication and signaling : CCS2025
The efferocytosis dilemma: how neutrophil extracellular traps and PI3K/Rac1 complicate diabetic wound healing.
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Mechanism and Component Study of Scorpion Peptides Regulation of Macrophage Polarization in Diabetic Wounds.Biomedicines · 2026Article
- A Manganese-Chlorella Hydrogel for an Integrated "Remove-Remodel-Repair" Strategy in Pancreatic Cancer Therapy.Nano-micro letters · 2026Article
- Polysaccharide-engineered mitochondria reprogram macrophages to resolve diabetic wound inflammation and promote repair.Bioactive materials · 2026Article
- Advances in Chinese herbal medicine for diabetic wound treatment: from tradition to innovation.Chinese medicine · 2026Review
- Cell death crosstalk in NET-Driven inflammation: mechanisms, disease contexts, and therapeutic perspectives.Biomarker research · 2026Review
- Review
- Neutrophils and neutrophil extracellular traps in diabetes mellitus and its complications: Mechanisms and therapeutic implications.iScience · 2026Review
- Roles of efferocytosis in wound repair: Process, cells, and signals.Genes & diseases · 2026Review
- Harnessing plant-derived extracellular vesicles in advanced biomaterials: from structural scaffolds to responsive systems for next-generation wound therapeutics.Burns & trauma · 2026Review
- Neutrophil Extracellular Traps in Wound Healing of Diabetes: Mechanisms, Inducers, and Therapeutic Implications.Mediators of inflammation · 2026Review
- The Crosstalk Between Efferocytosis and Macrophage Polarization in Diabetic Wounds: A Comprehensive Review.Journal of inflammation research · 2026Review
- Efferocytosis: unifying pathogenic hub in metabolic disorders-mechanistic landscapes, targeted therapies and translational bottlenecks.Frontiers in immunology · 2026Review
- Integrative neuromodulation in diabetic foot infections: electroacupuncture-driven macrophage reprogramming and synergy with antimicrobial biomaterials.Frontiers in cellular and infection microbiology · 2026Review
- Immune cells in diabetic wound repair: the key to better wound management.Frontiers of medicine · 2025Review
- Efferocytosis in Health and Disease.MedComm · 2025Review
- Topography-based implants for bone regeneration: Design, biological mechanism, and therapeutics.Materials today. Bio · 2025Review
- Beyond Killing: The Overlooked Contribution of Neutrophils to Tissue Repair.International journal of molecular sciences · 2025Review
- Glutamine metabolism and ammonia death: targeted modulation for enhanced cancer immunotherapy.Frontiers in immunology · 2025Review
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Authors and funding
5 authors.
Funding
Abstract
aims/hypothesisThe resolution of apoptotic cells (ACs) is crucial for wound healing and tissue remodeling and is often impaired by persistent inflammation. This study aimed to elucidate the impact of neutrophil extracellular traps (NETs) on diabetic wound healing by targeting the phosphoinositide 3-kinase/Ras-related C3 botulinum toxin substrate 1 (PI3K/Rac1) signaling pathway, which is pivotal for macrophage efferocytosis.
methodsA streptozotocin-induced diabetic mouse model was used to assess the impact of NETs on efferocytosis in vivo. The effects of NETs on macrophage efferocytosis and wound healing were evaluated using specific inhibitors and agonists targeting the PI3K/Rac1 pathway. In vitro, macrophages from diabetic wounds or cell lines (Raw264.7) were treated with NETs and a panel of pharmacological agents of the PI3K/Rac1 pathway to evaluate macrophage efferocytosis.
resultsNETs were found to inhibit macrophage efferocytosis, resulting in delayed clearance of ACs that accumulate within the wounds. Inhibition of NET formation in diabetic mice rescued impaired efferocytosis, accompanied by reactivation of PI3K and Rac1 in macrophages. Moreover, pharmacological agents targeting the PI3K/Rac1 pathway restored NETs-induced impairment in efferocytosis, leading to rapid wound healing. Raw264.7 cells exhibited elevated activation levels of PI3K and Rac1 when co-cultured with ACs in vitro. Nevertheless, this signaling activation was inhibited when cultured in a NETs-conditioned medium, leading to attenuated efferocytosis. CONCLUSIONS/
interpretationTargeting NETs and the PI3K/Rac1 pathway emerges as a potential therapeutic strategy to enhance healing in diabetic wounds by promoting macrophage efferocytosis.
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