Aging-induced IL27Ra signaling impairs hematopoietic stem cells
Aging-induced IL27Ra signaling impairs hematopoietic stem cells
复制标题
衰老诱导的 IL27Ra 信号传导损害造血干细胞。
DOI：
10.1182/blood.2019003910
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发表时间：
2020-07-09
期刊：
影响因子：
20.3
通讯作者：
Wang, Jianwei
中科院分区：
文献类型：
--
作者：
He, Hanqing;Xu, Panglian;Wang, Jianwei
造血干细胞（HSC）衰老与骨髓增生性疾病和免疫衰老的风险增加相关。在这项研究中，我们发现衰老相关的炎症通过肿瘤坏死因子-α（TNF-α）-> ERK -> ETS 1->白细胞介素27 Ra（IL 27 Ra）途径促进HSC衰老。TNF-α是一种众所周知的炎症生物标志物，在衰老过程中增加，并通过ERK-ETS 1信号转导诱导HSC上IL 27 Ra的表达。IL 27 Ra的缺失挽救了HSC的功能下降和髓样偏向，并且还逆转了TNF-α对HSC的抑制作用。老年IL 27 Ra（-/-）小鼠具有减少的骨髓偏向性HSC比例，并且没有显示出老年野生型小鼠中发生的偏向性骨髓分化。与IL 27 Ra（+）HSC相比，IL 27 Ra（+）HSC表现出受损的重建能力和骨髓偏向性，并在炎症损伤后作为骨髓恢复池。炎症相关基因在IL 27 Ra（+）HSC中富集，并且这种富集随着衰老而增加。我们的研究表明，年龄诱导的IL 27 Ra信号传导损害HSC，并提出了干扰IL 27 Ra信号传导可以对抗衰老对造血能力的生理有害影响的可能性。
Hematopoietic stem cell (HSC) aging correlates with an increasing risk of myeloproliferative disease and immunosenescence. In this study, we show that aging-related inflammation promotes HSC aging through tumor necrosis factor-alpha(TNF-alpha)-> ERK -> ETS1 -> interleukin27Ra (IL27Ra) pathway. TNF-alpha, a well-known biomarker of inflammation, increases during aging and induces the expression of IL27Ra on HSCs via ERK-ETS1 signaling. Deletion of IL27Ra rescues the functional decline and myeloid bias of HSCs and also reverses the inhibitory effect of TNF-alpha on HSCs. Aged IL27Ra(-/-) mice had a reduced proportion of myeloid-biased HSCs and did not display the biased myeloid differentiation that occurs in aged wild-type mice. IL27Ra(+) HSCs exhibit impaired reconstitution capacity and myeloid-bias compared with IL27Ra(+) HSCs and serve as a myeloid-recovery pool upon inflammatory insult. Inflammation-related genes were enriched in IL27Ra(+) HSCs and this enrichment increases with aging. Our study demonstrates that age-induced IL27Ra signaling impairs HSCs and raises the possibility that interfering with IL27Ra signaling can counter the physiologically deleterious effect of aging on hematopoietic capacity.