IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms
IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms
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DOI：
10.1172/jci77347
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发表时间：
2015-07-01
影响因子：
15.9
通讯作者：
Krebs, Philippe
中科院分区：
文献类型：
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作者：
Mager, Lukas F.;Riether, Carsten;Krebs, Philippe
骨髓增生性肿瘤（MPN）的特征在于一种或多种骨髓细胞谱系的克隆性扩增。在大多数情况下，恶性克隆的增殖归因于确定的遗传改变。MPN也与多种细胞因子的异常表达和活性相关;然而，这些细胞因子促进疾病发病机制的机制知之甚少。在这里，我们揭示了一个非冗余的作用，稳态IL-33在MPN的小鼠模型中支持失调的骨髓生成。IL-33信号通路的基因消除对于恢复正常造血和消除缺乏肌醇磷酸酶SHIP的动物中的MPN样疾病是充分和必要的。基质细胞来源的IL-33刺激骨髓和非造血细胞分泌细胞因子和生长因子，导致SHIP缺陷动物的骨髓增殖。此外，在转基因JAK 2（V617 F）模型中，在放射抗性细胞中缺乏IL-33的动物中，MPN的发作延迟。在人BM中，我们检测到IL-33表达细胞的数量增加，特别是在来自MPN患者的活检中。外源性IL-33促进患者的原代CD 34（+）MPN干/祖细胞的细胞因子产生和集落形成。此外，IL-33改善JAK 2（V617 F）阳性细胞系的存活。总之，这些数据表明IL-33信号传导在MPN发病机制中的核心作用。
Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2(V617F) model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33 expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34(+) MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2(V617F)-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.