Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Nat Commun. 2022 Sep 13;13(1):5347. doi: 10.1038/s41467-022-32928-3.
Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1β enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.
慢性炎症常与骨髓增殖性肿瘤（MPN）相关，但炎症在 MPN 发病机制中的作用仍不清楚。促炎细胞因子白细胞介素-1（IL-1）在 MPN 患者以及 Jak2V617F 基因敲入小鼠中表达升高。在这里，我们表明，IL-1 受体 1（IL-1R1）的基因缺失可使多发性骨髓瘤的同基因 Jak2V617F 小鼠模型的外周血细胞计数正常化，减少脾肿大并改善骨髓纤维化。IL-1R1 的缺失还显著减少了 Jak2V617F 突变造血干细胞/祖细胞。外源性给予 IL-1β 可增强髓样细胞扩增，并加速杂合子 Jak2V617F 小鼠骨髓纤维化的发展。此外，用抗 IL-1R1 抗体治疗可显著减少白细胞增多和脾肿大，并改善同基因 Jak2V617F 小鼠的骨髓纤维化。总之，这些结果表明 IL-1 信号在 MPN 疾病进展中起致病作用，靶向 IL-1R1 可能是治疗骨髓纤维化的有效策略。
Zotero 插件
