Ly6C(Hi) Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus.
Ly6C(Hi) Blood Monocyte/Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus.
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DOI：
10.1161/atvbaha.118.310703
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发表时间：
2018-05
期刊：
影响因子：
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通讯作者：
Gallagher KA
中科院分区：
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作者：
Kimball A;Schaller M;Joshi A;Davis FM;denDekker A;Boniakowski A;Bermick J;Obi A;Moore B;Henke PK;Kunkel SL;Gallagher KA
伤口单核细胞衍生的巨噬细胞可塑性控制炎症的启动和消退，这对于适当愈合至关重要，然而，在糖尿病中，炎症的消退未能发生。在糖尿病伤口中，血液单核细胞募集的动力学和控制体内单核细胞/巨噬细胞分化的机制仍然未知。在这里，我们表征了Ly 6CHi [Lin−（CD 3 − CD 19 −NK1.1−Ter-119−）Ly 6 G − CD 11b +]和Ly 6CLo [Lin−（CD 3 − CD 19 −NK1.1−Ter-119−）Ly 6 G − CD 11b +]单核细胞/巨噬细胞亚群在正常和糖尿病伤口中的动力学和功能。使用流式分选的tdTomato标记的Ly 6CHi单核细胞/巨噬细胞，我们显示Ly 6CHi细胞在正常伤口中转变为Ly 6CLo-表型，而在糖尿病伤口中，存在未能转变为Ly 6CLo的Ly 6CHi细胞的晚期第二次流入。糖尿病伤口中Ly 6CHi细胞的第二波对应于MCP-1的峰值，并且选择性施用抗MCP-1逆转了第二Ly 6CHi流入并改善了伤口愈合。为了检查伤口单核细胞/巨噬细胞的体内表型，对来自正常和糖尿病伤口的流式分选的Ly 6CHi [Lin-Ly 6 G-CD 11b +]和Ly 6CLo [Lin-Ly 6 G-CD 11b +]细胞进行基于RNA-seq的转录组分析。糖尿病伤口Ly 6CHi细胞的基因转录组谱显示与对照相比促炎基因和促纤维化基因的差异。总的来说，这些数据鉴定了糖尿病伤口单核细胞/巨噬细胞的动力学和功能差异，并证明选择性靶向CD 11b + Ly 6CHi单核细胞/巨噬细胞是糖尿病伤口炎症的可行治疗策略。
Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that are critical for proper healing, however, in diabetes, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood-monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown. Here, we characterized the kinetics and function of Ly6CHi[Lin− (CD3−CD19−NK1.1−Ter-119−)Ly6G−CD11b+] and Ly6CLo[Lin− (CD3−CD19−NK1.1−Ter-119−)Ly6G−CD11b+] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted tdTomato-labeled Ly6CHi monocyte/macrophages, we show Ly6CHi cells transition to a Ly6CLo- phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6CHi cells that fail transition to Ly6CLo. The second wave of Ly6CHi cells in diabetic wounds corresponded to a spike in MCP-1 and selective administration of anti-MCP-1 reversed the second Ly6CHi influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6CHi[Lin−Ly6G−CD11b+] and Ly6CLo[Lin−Ly6G−CD11b+] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6CHi cells demonstrated differences in pro-inflammatory and pro-fibrotic genes compared to controls. Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b+Ly6CHi monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.