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<p>Diabetic retinopathy (DR) is a common neurovascular complication of diabetes and a leading cause of vision loss in the advanced stages. Identifying therapeutic targets to prevent early progression of DR is critical for preserving visual function. Interleukin-12 (IL-12) has emerged as a potential therapeutic agent for early-stage diabetic retinal neurodegeneration. In this study, diabetic mouse models were established, followed by intravitreal injection of IL-12 to evaluate its effects using hematoxylin and eosin staining and RNA sequencing. IL-12 treatment partially prevented the thinning of the nerve fiber layer, ganglion cell layer, and total retina. Bioinformatics analysis of RNA sequencing data revealed enrichment of microglial signatures and enhanced phagocytic function. Western blotting analysis showed that IL-12 promoted the phosphorylation of signal transducer and activator of transcription 4 (STAT4) in microglia. Bioinformatics and quantitative reverse transcription polymerase chain reaction analyses demonstrated that STAT4 activation upregulated the transcription of phagocytosis-related genes, including triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12&#xa0;kDa (DAP12). In vitro and in vivo experiments confirmed that IL-12 upregulates the TREM2/DAP12 signaling pathway on the microglial membrane, enhancing microglial proliferation and phagocytic activity under high-glucose conditions. These findings indicated that IL-12 mitigates early neural injury in DR by promoting microglial phagocytosis through the upregulation of TREM2/DAP12.</p>

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IL-12 ameliorates diabetic retinal neurodegeneration by activating microglial phagocytosis via the TREM2/DAP12 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月29日

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  • Wanyi Fang,
  • Shanshan Liu,
  • Yifei Wu,
  • Ting Chen,
  • Xiaohe Lu,
  • Hui Chen

摘要

Diabetic retinopathy (DR) is a common neurovascular complication of diabetes and a leading cause of vision loss in the advanced stages. Identifying therapeutic targets to prevent early progression of DR is critical for preserving visual function. Interleukin-12 (IL-12) has emerged as a potential therapeutic agent for early-stage diabetic retinal neurodegeneration. In this study, diabetic mouse models were established, followed by intravitreal injection of IL-12 to evaluate its effects using hematoxylin and eosin staining and RNA sequencing. IL-12 treatment partially prevented the thinning of the nerve fiber layer, ganglion cell layer, and total retina. Bioinformatics analysis of RNA sequencing data revealed enrichment of microglial signatures and enhanced phagocytic function. Western blotting analysis showed that IL-12 promoted the phosphorylation of signal transducer and activator of transcription 4 (STAT4) in microglia. Bioinformatics and quantitative reverse transcription polymerase chain reaction analyses demonstrated that STAT4 activation upregulated the transcription of phagocytosis-related genes, including triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12). In vitro and in vivo experiments confirmed that IL-12 upregulates the TREM2/DAP12 signaling pathway on the microglial membrane, enhancing microglial proliferation and phagocytic activity under high-glucose conditions. These findings indicated that IL-12 mitigates early neural injury in DR by promoting microglial phagocytosis through the upregulation of TREM2/DAP12.