Type I IFNs drive hematopoietic stem and progenitor cell collapse via impaired proliferation and increased RIPK1-dependent cell death during shock-like ehrlichial infection.
Type I IFNs drive hematopoietic stem and progenitor cell collapse via impaired proliferation and increased RIPK1-dependent cell death during shock-like ehrlichial infection.
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DOI：
10.1371/journal.ppat.1007234
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发表时间：
2018-08
期刊：
影响因子：
6.7
通讯作者：
MacNamara KC
中科院分区：
文献类型：
--
作者：
Smith JNP;Zhang Y;Li JJ;McCabe A;Jo HJ;Maloney J;MacNamara KC
I型干扰素（IFNα/β）调节宿主防御的各个方面，但它们在感染期间对造血干细胞和祖细胞（HSC/HSPCs）的影响仍不清楚。严重感染时可能发生血液学损伤，因此我们试图研究I型IFN对蜱传感染引起休克样疾病的毒性埃立克体病原体的造血的影响。在感染期间，IFNα/β诱导严重的骨髓（BM）丢失，钝化感染诱导的紧急骨髓生成，并减少表型HSPC和HSC。在缺乏I型IFN信号的情况下，BM和脾造血增加，并且来自Ifnar 1缺陷小鼠的HSC在竞争性BM移植中在功能上是上级的。I型IFN在感染期间通过限制HSC/HSPC增殖和增加HSPC死亡而损害造血。使用混合BM嵌合体，我们确定I型IFN间接限制增殖，而HSPC死亡通过直接IFNαR介导的信号传导发生。相对于Ifnar 1缺陷小鼠，IFNα R依赖性信号导致半胱天冬酶8表达和活性降低，以及RIPK 1和RIPK 3的切割降低。RIPK 1拮抗Necrostatin-1在感染期间挽救了HSPC和HSC数量。小鼠存活需要早期抗生素治疗，然而，抗生素治疗的存活者的HSPC和HSC严重减少。与单独抗生素治疗相比，抗生素和Necrostatin-1的联合治疗改善了存活小鼠中的HSPC和HSC数量。我们揭示了两种机制，即I型干扰素驱动造血崩溃在严重感染：直接致敏HSPCs进行细胞死亡和增强HSC静止。我们的研究揭示了改善感染期间HSC和HSPC的I型IFN依赖性损失的策略，这可能与其中I型IFN引起造血功能障碍的其他感染相关。埃立克体是重要的新兴蜱传病原体，可引起免疫抑制和血细胞减少，但其潜在机制尚不清楚。在由卵形硬蜱埃里希体引起的休克样疾病的模型中，I型干扰素（IFN）通过减少造血干细胞（HSC）增殖和驱动造血祖细胞（HSPC）的细胞死亡来诱导造血功能障碍。使用混合骨髓嵌合体，我们表明，HSPC损失发生通过内在I型IFN信号，而HSC增殖是通过外在机制调节。与无菌性炎症相反，感染诱导的I型IFN诱导造血祖细胞的RIPK 1依赖性损失。在感染期间，通过用Necrostatin-1 s抑制RIPK 1来拯救HSPC。虽然抗生素治疗保护免受其他致命感染，但从感染中恢复的小鼠表现出显著减少的HSC和HSPC。与单独使用抗生素相比，抗生素和Necrostatin-1的联合治疗显著增加了HSPC频率和HSC数量。血液生产是生命所必需的，也是宿主防御所必需的，因此我们的工作揭示了一种治疗策略，以拯救和改善严重感染性疾病患者的造血功能。
Type I interferons (IFNα/β) regulate diverse aspects of host defense, but their impact on hematopoietic stem and progenitor cells (HSC/HSPCs) during infection remains unclear. Hematologic impairment can occur in severe infections, thus we sought to investigate the impact of type I IFNs on hematopoiesis in a tick-borne infection with a virulent ehrlichial pathogen that causes shock-like disease. During infection, IFNα/β induced severe bone marrow (BM) loss, blunted infection-induced emergency myelopoiesis, and reduced phenotypic HSPCs and HSCs. In the absence of type I IFN signaling, BM and splenic hematopoiesis were increased, and HSCs derived from Ifnar1-deficient mice were functionally superior in competitive BM transplants. Type I IFNs impaired hematopoiesis during infection by both limiting HSC/HSPC proliferation and increasing HSPC death. Using mixed BM chimeras we determined that type I IFNs restricted proliferation indirectly, whereas HSPC death occurred via direct IFNαR -mediated signaling. IFNαR-dependent signals resulted in reduced caspase 8 expression and activity, and reduced cleavage of RIPK1 and RIPK3, relative to Ifnar1-deficient mice. RIPK1 antagonism with Necrostatin-1s rescued HSPC and HSC numbers during infection. Early antibiotic treatment is required for mouse survival, however antibiotic-treated survivors had severely reduced HSPCs and HSCs. Combination therapy with antibiotics and Necrostatin-1s improved HSPC and HSC numbers in surviving mice, compared to antibiotic treatment alone. We reveal two mechanisms whereby type I IFNs drive hematopoietic collapse during severe infection: direct sensitization of HSPCs to undergo cell death and enhanced HSC quiescence. Our studies reveal a strategy to ameliorate the type I IFN-dependent loss of HSCs and HSPCs during infection, which may be relevant to other infections wherein type I IFNs cause hematopoietic dysfunction. The Ehrlichiae are important emerging, tick-borne pathogens that cause immune suppression and cytopenias, though the underlying mechanisms are unclear. In a model of shock-like illness caused by Ixodes ovatus ehrlichia, type I interferons (IFNs) induce hematopoietic dysfunction by reducing hematopoietic stem cell (HSC) proliferation and driving cell death of hematopoietic progenitors (HSPCs). Using mixed bone marrow chimeras, we demonstrate that HSPC loss occurs via intrinsic type I IFN signaling, whereas HSC proliferation is regulated via an extrinsic mechanism. In contrast to sterile inflammation, infection-induced type I IFNs induced RIPK1-dependent loss of hematopoietic progenitors. HSPCs were rescued during infection by inhibiting RIPK1 with Necrostatin-1s. While antibiotic treatment protected against otherwise lethal infection, mice recovering from infection exhibited significantly reduced HSCs and HSPCs. Co-treatment with both antibiotics and Necrostatin-1s significantly increased HSPC frequencies and the number of HSCs compared to antibiotics alone. Blood production is essential for life and necessary for host defense, thus our work reveals a therapeutic strategy to rescue and improve hematopoiesis in patients recovering from serious infectious disease.
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