The Healing Foundation Centre, Faculty of Life Sciences, University of Manchester, Manchester, U.K.
Faculty of Medical and Human Sciences, University of Manchester, Manchester, U.K.
Diabetes. 2015 Dec;64(12):4184-97. doi: 10.2337/db14-1895. Epub 2015 Aug 31.
Recruitment of innate immune cells from the bone marrow (BM) to an injury site is required for effective repair. In diabetes, this process is altered, leading to excessive recruitment and retention of dysfunctional myeloid cells that fail to promote angiogenesis, prolong inflammation, and block healing. The aberrant myeloid phenotype is partially mediated by stable intrinsic changes to developing cells in the BM that are induced by the diabetic (db) environment, but the exact mechanisms remain largely unknown. Here, we show that the db-derived Gr-1(+)CD11b(+) immature myeloid population has widespread misexpression of chromatin-remodeling enzymes and myeloid differentiation factors. Crucially, diabetes represses transcription of the key myeloid transcription factor CEBPA via diminished H3 Lys 27 promoter acetylation, leading to a failure in monocyte and granulocyte maturation. Restoring Cebpa expression by granulocyte colony-stimulating factor reverses the db phenotype and rescues myeloid maturation. Importantly, our data demonstrate a possible link between myeloid cell maturation and chronic inflammation.
招募骨髓中的先天免疫细胞到损伤部位是有效修复所必需的。在糖尿病中，这个过程发生了改变，导致功能失调的髓样细胞过度募集和滞留，这些细胞无法促进血管生成、延长炎症反应并阻碍愈合。这种异常的髓样表型部分是由糖尿病（db）环境诱导的骨髓中发育中的细胞的稳定内在变化介导的，但确切的机制仍在很大程度上未知。在这里，我们表明，db 来源的 Gr-1(+)CD11b(+)未成熟髓样细胞群体广泛表达染色质重塑酶和髓样分化因子。至关重要的是，糖尿病通过减少 H3 Lys 27 启动子乙酰化来抑制关键髓样转录因子 CEBPA 的转录，导致单核细胞和粒细胞成熟失败。通过粒细胞集落刺激因子恢复 Cebpa 表达可逆转 db 表型并挽救髓样细胞成熟。重要的是，我们的数据表明髓样细胞成熟与慢性炎症之间可能存在联系。
