Wnt5a Inhibits Human Monocyte-Derived Myeloid Dendritic Cell Generation
Wnt5a Inhibits Human Monocyte-Derived Myeloid Dendritic Cell Generation
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DOI：
10.1111/sji.12075
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发表时间：
2013-08-01
影响因子：
3.7
通讯作者：
Leandersson, K.
中科院分区：
文献类型：
--
作者：
Bergenfelz, C.;Janols, H.;Leandersson, K.
Wnt 5a是一种非典型的Wnt蛋白，在炎症条件下以升高的水平表达。其在炎症中的作用仍不清楚，尽管已知Wnt 5a在单核细胞衍生的髓样树突状细胞（Mo-mDC）中的表达水平高于单核细胞和巨噬细胞。Wnt 5a在树突状细胞（DC）中的功能仍然相对未被探索。在此，我们发现在Mo-mDC培养条件下，Wnt 5a抑制CD 14（+/低）Mo-mDC的产生，同时促进CD 14（+/++）CD 16（+）单核细胞的产生。我们可以进一步表明，用rWnt 5a刺激单核细胞诱导快速IL-6产生，并且在阻断IL-6后，rWnt 5a处理的Mo-mDC分化恢复。此外，来自Wnt 5a的条件培养基刺激人乳腺癌细胞产生IL-6，特异性抑制Mo-mDC分化。我们发现脓毒症患者（一种涉及升高的Wnt 5a和IL-6水平的疾病）也显示出CD 14（+）CD 16（++）/CD 14（+/++）CD 16（+）单核细胞群的显著增加，这伴随着循环mDC的显著减少，从而加强了这些观察结果。我们最终表明，在典型的Mo-mDC培养条件下，与健康对照相比，从脓毒症患者分离的单核细胞优先分化为CD 14（+/++）HLA-DR++细胞。我们认为Wnt 5a可能是感染性疾病和癌症患者中CD 14（+/++）CD 16（+）单核细胞积聚的候选介质。
Wnt5a is a non-canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte-derived myeloid dendritic cells (Mo-mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo-mDC culture conditions, Wnt5a inhibited the generation of CD14(+/low) Mo-mDCs while promoting the generation of CD14(+/++)CD16(+) monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL-6 production and that the rWnt5a treated Mo-mDC differentiation was restored upon blocking of IL-6. Also, conditioned media from Wnt5a stimulated human breast cancer cells producing IL-6, specifically inhibited Mo-mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL-6 levels, also showed a significant increase in the CD14(+)CD16(++)/CD14(+/++)CD16(+) monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo-mDC culture conditions, monocytes isolated from patients with sepsis as compared to healthy controls, preferentially differentiated into CD14(+/++)HLA-DR++ cells. We suggest that Wnt5a is a possible candidate mediator for the CD14(+/++)CD16(+) monocyte accumulation seen in patients with infectious disease and cancer.