Ripk3 signaling regulates HSCs during stress and represses radiation-induced leukemia in mice.
Ripk3 signaling regulates HSCs during stress and represses radiation-induced leukemia in mice.
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DOI：
10.1016/j.stemcr.2022.04.009
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发表时间：
2022-06-14
影响因子：
5.9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhang L;Luo H;Ni HM;Liu S;Xing H;Zhang J;Sellin M;Breslin S J P;Wei W;Denning MF;Small W Jr;Ding WX;Huang S;Zhang J
受体相互作用蛋白激酶3（Ripk 3）是炎症介质中的一个关键介导因子。在这里，我们表明，Ripk 3信号选择性地调节造血干细胞（HSC）的数量和功能在应激条件下。Ripk 3信号传导不是正常稳态造血所必需的。然而，响应于连续移植，Ripk 3信号传导的失活防止应激诱导的HSC耗尽和功能性HSC衰减，而响应于分次低剂量电离辐射（IR），Ripk 3信号传导的失活加速白血病/淋巴瘤的发展。在这两种情况下，Ripk 3信号主要由肿瘤坏死因子-α刺激。活化的Ripk 3信号传导通过诱导Mlkl依赖性坏死性凋亡促进连续移植期间HSC和分级IR期间前白血病干细胞（pre-LSC）的消除。活化的Ripk 3信号传导还减弱HSC功能并通过促进Mlkl非依赖性衰老来抑制前LSC向LSC的转化。此外，我们证明Ripk 3信号通过减弱ISR介导的线粒体质量控制诱导HSC和前LSC衰老。Ripk 3-Mlkl信号传导不是正常稳态造血所需的Ripk 3-Mlkl信号传导促进连续移植期间的HSC损失或低剂量IR Tnf-α-Ripk 3信号传导在暴露于低剂量IR后防止白血病发展Ripk 3通过诱导Mlkl坏死性凋亡和PDC-OXPHOS-ROS衰老来抑制前LSC。等报道，尽管Ripk 3-Mlkl信号传导不是正常稳态造血所需的，但其在连续移植或低剂量照射（IR）期间引起HSC损失。由于前LSC中Mlkl坏死性凋亡和PDC-OXPHOS-ROS衰老途径的损伤，HSC中Ripk 3的失活加速了小鼠中低剂量IR诱导的白血病发展。
Receptor-interacting protein kinase 3 (Ripk3) is one of the critical mediators of inflammatory cytokine-stimulated signaling. Here we show that Ripk3 signaling selectively regulates both the number and the function of hematopoietic stem cells (HSCs) during stress conditions. Ripk3 signaling is not required for normal homeostatic hematopoiesis. However, in response to serial transplantation, inactivation of Ripk3 signaling prevents stress-induced HSC exhaustion and functional HSC attenuation, while in response to fractionated low doses of ionizing radiation (IR), inactivation of Ripk3 signaling accelerates leukemia/lymphoma development. In both situations, Ripk3 signaling is primarily stimulated by tumor necrosis factor-α. Activated Ripk3 signaling promotes the elimination of HSCs during serial transplantation and pre-leukemia stem cells (pre-LSCs) during fractionated IR by inducing Mlkl-dependent necroptosis. Activated Ripk3 signaling also attenuates HSC functioning and represses a pre-LSC-to-LSC transformation by promoting Mlkl-independent senescence. Furthermore, we demonstrate that Ripk3 signaling induces senescence in HSCs and pre-LSCs by attenuating ISR-mediated mitochondrial quality control. Ripk3-Mlkl signaling is not required for normal homeostatic hematopoiesis Ripk3-Mlkl signaling promotes HSC loss during serial transplantation or low-dose IR Tnf-α-Ripk3 signaling prevents leukemia development after exposure to low-dose IR Ripk3 represses pre-LSCs by inducing Mlkl necroptosis and PDC-OXPHOS-ROS senescence In this article, Zhang et al. report that, although Ripk3-Mlkl signaling is not required for normal homeostatic hematopoiesis, it causes HSC loss during serial transplantation or low-dose irradiation (IR). Inactivation of Ripk3 in HSCs accelerates low-dose IR-induced leukemia development in mice due to impairment of Mlkl necroptotic and PDC-OXPHOS-ROS senescence pathways in pre-LSCs.
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caspase-8脚手架函数和MLKL调节TLR3下游的NLRP3炎性体激活。
影响因子：
16.6
作者：
Kang, Seokwon;Fernandes-Alnemri, Teresa;Rogers, Corey;Mayes, Lindsey;Wang, Ying;Dillon, Christopher;Roback, Linda;Kaiser, William;Oberst, Andrew;Sagara, Junji;Fitzgerald, Katherine A.;Green, Douglas R.;Zhang, Jianke;Mocarski, Edward S.;Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.
凋亡启动和 ATM 信号传导的减弱赋予衰老造血干细胞响应 DNA 损伤的生存优势。
影响因子：
21.3
作者：
Gutierrez-Martinez P;Hogdal L;Nagai M;Kruta M;Singh R;Sarosiek K;Nussenzweig A;Beerman I;Letai A;Rossi DJ
通讯作者：
Rossi DJ
影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
DOI：
10.4049/jimmunol.1701492
发表时间：
2018-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Brault M;Olsen TM;Martinez J;Stetson DB;Oberst A
通讯作者：
Oberst A
影响因子：
32.4
作者：
Moriwaki, Kenta;Balaji, Sakthi;McQuade, Thomas;Malhotra, Nidhi;Kang, Joonsoo;Chan, Francis Ka-Ming
通讯作者：
Chan, Francis Ka-Ming