Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models.
Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models.
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在红细胞增多症小鼠模型中，通过升高 EPOR 信号使 EPOR 阴性巨噬细胞扩增至成红细胞之外
DOI：
10.3324/haematol.2017.172775
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发表时间：
2018-01
期刊：
影响因子：
10.1
通讯作者：
Huang G
中科院分区：
文献类型：
--
作者：
Wang J;Hayashi Y;Yokota A;Xu Z;Zhang Y;Huang R;Yan X;Liu H;Ma L;Azam M;Bridges JP;Cancelas JA;Kalfa TA;An X;Xiao Z;Huang G
激活的促红细胞生成素（EPO）受体（EPOR）信号传导引起红细胞增多。巨噬细胞在红细胞扩增和分化过程中的重要作用已被报道，无论是在基线和应激红细胞生成。然而，EPOR信号调节巨噬细胞促进红细胞生成的意义尚未完全理解。在这里，我们表明，EPOR信号激活迅速扩大红细胞和巨噬细胞在体内的小鼠模型的原发性和继发性红细胞增多症。为了模拟嵌合状态和真性红细胞增多症患者中疾病克隆的扩增，我们将Cre诱导的Jak 2 V617 F/+等位基因与在成熟骨髓细胞和一些HSC/Ps中表达的LysM-Cre等位基因（LysM-Cre; Jak 2 V617 F/+小鼠）组合。我们还使用Alb-Cre、Rosa 26-loxP-stop-loxP-rtTA和多西环素诱导的EPAS 1-双点突变（doxycycline inducible EPAS 1-double point mutant，doxycycline）等位基因产生了诱导型EPO介导的继发性红细胞增多症模型（Alb-Cre; doxycycline mice）。两种模型均出现了相似程度的红细胞增多。在两种模型中，巨噬细胞也增加，而主要炎性细胞因子和趋化因子没有增加。在可观察到红细胞增多之前，EPO给药也快速诱导野生型小鼠中的这些巨噬细胞。这些结果表明，EPOR信号激活不仅可以诱导红系细胞扩增，而且可以诱导巨噬细胞。令人惊讶的是，体内遗传学方法表明，这些巨噬细胞中的大多数不表达EPOR，但红系细胞和巨噬细胞彼此紧密接触。考虑到中央巨噬细胞作为红细胞生成的生态位的重要性，进一步阐明EPOR信号介导的巨噬细胞诱导的调控机制可能揭示红细胞增多症的潜在治疗靶点。
Activated erythropoietin (EPO) receptor (EPOR) signaling causes erythrocytosis. The important role of macrophages for the erythroid expansion and differentiation process has been reported, both in baseline and stress erythropoiesis. However, the significance of EPOR signaling for regulation of macrophages contributing to erythropoiesis has not been fully understood. Here we show that EPOR signaling activation quickly expands both erythrocytes and macrophages in vivo in mouse models of primary and secondary erythrocytosis. To mimic the chimeric condition and expansion of the disease clone in the polycythemia vera patients, we combined Cre-inducible Jak2V617F/+ allele with LysM-Cre allele which expresses in mature myeloid cells and some of the HSC/Ps (LysM-Cre;Jak2V617F/+ mice). We also generated inducible EPO-mediated secondary erythrocytosis models using Alb-Cre, Rosa26-loxP-stop-loxP-rtTA, and doxycycline inducible EPAS1-double point mutant (DPM) alleles (Alb-Cre;DPM mice). Both models developed a similar degree of erythrocytosis. Macrophages were also increased in both models without increase of major inflammatory cytokines and chemokines. EPO administration also quickly induced these macrophages in wild-type mice before observable erythrocytosis. These findings suggest that EPOR signaling activation could induce not only erythroid cell expansion, but also macrophages. Surprisingly, an in vivo genetic approach indicated that most of those macrophages do not express EPOR, but erythroid cells and macrophages contacted tightly with each other. Given the importance of the central macrophages as a niche for erythropoiesis, further elucidation of the EPOR signaling mediated-regulatory mechanisms underlying macrophage induction might reveal a potential therapeutic target for erythrocytosis.
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