IRF8 Impacts Self-Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells.
IRF8 Impacts Self-Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells.
复制标题
IRF8 通过调节先天免疫细胞的 TLR9 信号通路影响造血干细胞的自我更新。
DOI：
10.1002/advs.202101031
复制
发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Ren R
中科院分区：
文献类型：
--
作者：
Li D;Zhang Y;Qiu Q;Wang J;Zhao X;Jiao B;Zhang X;Yu S;Xu P;Dan Y;Xiao X;Wang P;Liu M;Xia Z;Huang Z;Zhang R;Li J;Xie X;Zhang Y;Liu C;Liu P;Ren R
IRF 8是先天免疫受体信号传导的关键调节因子，在造血细胞的发育中发挥多种功能。IRF 8对造血干细胞（HSC）的影响仍然未知。在此，证明了IRF 8缺乏导致小鼠中长期HSC（LT-HSC）的数量减少。然而，单个HSC的再增殖能力显著增加。转录组学分析显示，IFN-γ和IFN-α信号在IRF 8缺陷型HSC中下调，而它们对促炎细胞因子的反应在体外没有变化。进一步的测试表明，Irf 8 −/− HSC不能对小鼠Toll样受体9（TLR 9）的激动剂CpG产生反应，而长期CpG刺激增加了野生型HSC的丰度，降低了它们的骨髓集落形成能力。从机制上讲，作为响应CpG刺激的促炎细胞因子的主要生产者，树突状细胞由于Irf 8 −/−小鼠的发育缺陷而阻断了TLR 9信号传导。巨噬细胞在功能上保持完整，但在Irf 8 −/−小鼠中严重减少。在NK细胞中，IRF 8直接调节Tlr 9的表达，其缺陷导致CpG刺激后IFNγ产生不增加。这些结果表明，IRF 8至少部分地通过控制不同先天免疫细胞中的TLR 9信号传导来调节HSC。这项研究揭示了IRF 8功能对造血干细胞（HSC）的影响。Irf 8 −/−小鼠表现出减少的HSC数量，但增强了HSC的再增殖能力。在机制上，IRF 8通过控制单核细胞/巨噬细胞和树突细胞的发育以及NK细胞中TLR 9的表达来影响促炎细胞因子的释放。因此，细胞因子介导的HSC增殖和耗竭减少。
IRF8 is a key regulator of innate immunity receptor signaling and plays diverse functions in the development of hematopoietic cells. The effects of IRF8 on hematopoietic stem cells (HSCs) are still unknown. Here, it is demonstrated that IRF8 deficiency results in a decreased number of long‐term HSCs (LT‐HSCs) in mice. However, the repopulation capacity of individual HSCs is significantly increased. Transcriptomic analysis shows that IFN‐γ and IFN‐α signaling is downregulated in IRF8‐deficient HSCs, while their response to proinflammatory cytokines is unchanged ex vivo. Further tests show that Irf8 −/− HSCs can not respond to CpG, an agonist of Toll‐like receptor 9 (TLR9) in mice, while long‐term CpG stimulation increases wild‐type HSC abundance and decreases their bone marrow colony‐forming capacity. Mechanistically, as the primary producer of proinflammatory cytokines in response to CpG stimulation, dendritic cells has a blocked TLR9 signaling due to developmental defect in Irf8 −/− mice. Macrophages remain functionally intact but severely reduce in Irf8 −/− mice. In NK cells, IRF8 directly regulates the expression of Tlr9 and its deficiency leads to no increased IFNγ production upon CpG stimulation. These results indicate that IRF8 regulates HSCs, at least in part, through controlling TLR9 signaling in diverse innate immune cells. This study reveals the effects of IRF8 function on hematopoietic stem cells (HSCs). Irf8 −/− mice exhibit a decrease number yet enhanced repopulation capacity of HSCs. Mechanistically, IRF8 affects the release of proinflammatory cytokines by controlling the development of monocytes/macrophages and dendritic cells and the expression of TLR9 in NK cells. Consequently, the cytokine‐mediated HSC proliferation and exhaustion are reduced.
登录
查看更多内容
影响因子：
64.5
作者：
Karki R;Lee E;Place D;Samir P;Mavuluri J;Sharma BR;Balakrishnan A;Malireddi RKS;Geiger R;Zhu Q;Neale G;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
20.3
作者：
Jo, Seung-Hee;Schatz, Jonathan H.;Ren, Ruibao
通讯作者：
Ren, Ruibao
影响因子：
16
作者：
Bornstein C;Winter D;Barnett-Itzhaki Z;David E;Kadri S;Garber M;Amit I
通讯作者：
Amit I
影响因子：
10.5
作者：
Mancino A;Termanini A;Barozzi I;Ghisletti S;Ostuni R;Prosperini E;Ozato K;Natoli G
通讯作者：
Natoli G
影响因子：
15.9
作者：
Bowie, Michelle B.;McKnight, Kristen D.;Eaves, Connie J.
通讯作者：
Eaves, Connie J.