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,Advanced Science

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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
Advanced Science ( IF 14.3 ) Pub Date : 2021-08-08 , DOI: 10.1002/advs.202101031
Donghe Li ₁ , Yuyin Zhang ₁ , Qingsong Qiu ₁ , Jinzeng Wang ₁ , Xuemei Zhao ₁ , Bo Jiao ₁ , Xiuli Zhang ₁ , Shanhe Yu ₁ , Pengfei Xu ₁ , Yuqing Dan ₁ , Xinhua Xiao ₁ , Peihong Wang ₁ , Mingzhu Liu ₁ , Zhizhou Xia ₁ , Zhangsen Huang ₁ , Ruihong Zhang ₁ , Jiaoyang Li ₁ , Xi Xie ₁ , Yan Zhang ₁ , Chenxuan Liu ₁ , Ping Liu ₁ , Ruibao Ren ₁

Affiliation

IRF8 是先天免疫受体信号传导的关键调节因子，在造血细胞发育中发挥多种功能。IRF8 对造血干细胞 (HSC) 的影响仍然未知。在这里，证明了 IRF8 缺乏导致小鼠中长期 HSC (LT-HSC) 的数量减少。然而，单个 HSC 的再增殖能力显着增加。转录组学分析表明，在 IRF8 缺陷型 HSC 中， IFN- γ和 IFN- α信号传导下调，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Irf8 ^-/-HSC 对 CpG 没有反应，CpG 是小鼠中 Toll 样受体 9 (TLR9) 的激动剂，而长期 CpG 刺激会增加野生型 HSC 的丰度并降低其骨髓集落形成能力。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Irf8 ^-/-小鼠的发育缺陷而具有阻断的 TLR9 信号传导。巨噬细胞在Irf8 ^-/-小鼠中保持功能完整，但严重减少。在 NK 细胞中，IRF8 直接调节Tlr9的表达，其缺乏导致 IFN γ不增加在 CpG 刺激下产生。这些结果表明，IRF8 至少部分通过控制多种先天免疫细胞中的 TLR9 信号传导来调节 HSC。

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IRF8 Impacts Self-Renewal of Hematopoietic Stem Cells by Regulating TLR9 Signaling Pathway of Innate Immune Cells

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.

更新日期：2021-10-08

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