间充质干细胞
前列腺素D2
癌症研究
造血
祖细胞
FOXP3型
先天性淋巴细胞
炎症
免疫学
生物
白血病
细胞生物学
干细胞
受体
先天免疫系统
免疫系统
生物化学
作者
Limei Wu,Qiqi Lin,Zhilin Ma,Fabliha Ahmed Chowdhury,Habibul Hasan Mazumder,Wei Du
出处
期刊:Leukemia
[Springer Nature]
日期:2020-05-04
卷期号:34 (11): 3028-3041
被引量:22
标识
DOI:10.1038/s41375-020-0843-8
摘要
Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD2 has recently emerged as a key regulator of tumor- and inflammation-associated functions. Here we show that mesenchymal stromal cells (MSCs) from patients with acute myeloid leukemia (AML) or normal MSCs overexpressing COX2 promote proliferation of co-cultured hematopoietic stem and progenitor cells (HSPCs), which can be prevented by treatment with COX2 knockdown or TM30089, a specific antagonist of the PGD2 receptor CRTH2. Mechanistically, we demonstrate that PGD2-CRTH2 signaling acts directly on type 2 innate lymphoid cells (ILC2s), potentiating their expansion and driving them to produce Interleukin-5 (IL-5) and IL-13. Furthermore, IL-5 but not IL-13 expands CD4+CD25+IL5Rα+ T regulatory cells (Tregs) and promotes HSPC proliferation. Disruption of the PGD2-activated ILC2-Treg axis by specifically blocking the PGD2 receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of CD4+CD25+IL5Rα+ Tregs promotes malignant HSPC proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD2 promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this novel PGD2-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases.
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