Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients
Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients
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DOI：
10.4049/jimmunol.1103378
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发表时间：
2012-06-01
影响因子：
4.4
通讯作者：
Leandersson, Karin
中科院分区：
文献类型：
--
作者：
Bergenfelz, Caroline;Medrek, Catharina;Leandersson, Karin
精心策划的炎症反应包括诱导效应功能，并在后期主动下调这一潜在有害过程。在这项研究中，我们发现在促炎条件下，非典型Wnt蛋白Wnt5a诱导免疫抑制巨噬细胞。Wnt5a诱导的抑制性表型与诱导IL-10和抑制经典tlr4 - nf - κ B信号有关。有趣的是，这种表型与败血症患者重编程单核细胞中观察到的表型非常相似。wnt5a诱导的反馈抑制在体外LPS刺激巨噬细胞和含有LPS的革兰氏阴性菌引起的脓毒症患者中都是活跃的。此外，通过使用乳腺癌患者组织微阵列，我们发现Wnt5a在恶性上皮细胞中的表达与CD163（+）抗炎肿瘤相关巨噬细胞的频率之间存在很强的相关性。总之，我们的数据指出Wnt5a是脓毒症和恶性肿瘤等多种严重人类疾病有效治疗方式的潜在靶点。中华免疫学杂志，2012,18(8):5448-5458。
A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-kappa B signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy. The Journal of Immunology, 2012, 188: 5448-5458.