Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA.
Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China.
Leukemia. 2020 Nov;34(11):3028-3041. doi: 10.1038/s41375-020-0843-8. Epub 2020 May 4.
Cyclooxygenase (COX)-dependent production of prostaglandins (PGs) is known to play important roles in tumorigenesis. PGD 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 PGD receptor CRTH2. Mechanistically, we demonstrate that PGD-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 CD4CD25IL5Rα T regulatory cells (Tregs) and promotes HSPC proliferation. Disruption of the PGD-activated ILC2-Treg axis by specifically blocking the PGD receptor CRTH2 or IL-5 impedes proliferation of normal and malignant HSPCs. Conversely, co-transfer of CD4CD25IL5Rα Tregs promotes malignant HSPC proliferation and accelerates leukemia development in xenotransplanted mice. Collectively, these results indicate that the mesenchymal source of PGD promotes proliferation of normal and malignant HSPCs through activation of the ILC2-Treg axis. These findings also suggest that this novel PGD-activated ILC2-Treg axis may be a valuable therapeutic target for cancer and inflammation-associated diseases.
环氧化酶（COX）依赖性前列腺素（PGs）的产生已知在肿瘤发生中起重要作用。PGD 最近已成为肿瘤和炎症相关功能的关键调节剂。在这里，我们表明急性髓细胞性白血病（AML）患者的间充质基质细胞（MSC）或过表达 COX2 的正常 MSC 可促进共培养的造血干祖细胞（HSPC）的增殖，这可通过 COX2 敲低或 TM30089 治疗来预防，TM30089 是 PGD 受体 CRTH2 的特异性拮抗剂。从机制上讲，我们证明了 PGD-CRTH2 信号直接作用于 2 型先天淋巴样细胞（ILC2），增强其扩增并促使它们产生白细胞介素-5（IL-5）和白细胞介素-13（IL-13）。此外，IL-5 但不是 IL-13 可扩增 CD4CD25IL5Rα T 调节细胞（Tregs）并促进 HSPC 增殖。通过特异性阻断 PGD 受体 CRTH2 或 IL-5 破坏 PGD 激活的 ILC2-Treg 轴可阻碍正常和恶性 HSPC 的增殖。相反，共转移 CD4CD25IL5Rα Tregs 可促进恶性 HSPC 的增殖并加速异种移植小鼠中的白血病发展。总之，这些结果表明 PGD 的间质来源通过激活 ILC2-Treg 轴促进正常和恶性 HSPC 的增殖。这些发现还表明，这种新型的 PGD 激活的 ILC2-Treg 轴可能是癌症和炎症相关疾病的有价值的治疗靶标。
