Hematopoietic stem cells (HSCs) maintain a quiescent state during homeostasis, but with acute infection, they exit the quiescent state to increase the output of immune cells, the so-called “emergency hematopoiesis.” However, HSCs’ response to severe infection during septic shock and the pathological impact remain poorly elucidated. Here, we report that the histone demethylase KDM1A/LSD1, serving as a critical regulator of mammalian hematopoiesis, is a negative regulator of the response to inflammation in HSCs during endotoxic shock typically observed during acute bacterial or viral infection. Inflammation-induced LSD1 deficiency results in an acute expansion of a pathological population of hyperproliferative and hyperinflammatory myeloid progenitors, resulting in a septic shock phenotype and acute death. Unexpectedly, in vivo administration of bacterial lipopolysaccharide (LPS) to wild-type mice results in acute suppression of LSD1 in HSCs with a septic shock phenotype that resembles that observed following induced deletion of LSD1. The suppression of LSD1 in HSCs is caused, at least in large part, by a cohort of inflammation-induced microRNAs. Significantly, reconstitution of mice with bone marrow progenitor cells expressing inhibitors of these inflammation-induced microRNAs blocked the suppression of LSD1 in vivo following acute LPS administration and prevented mortality from endotoxic shock. Our results indicate that LSD1 activators or miRNA antagonists could serve as a therapeutic approach for life-threatening septic shock characterized by dysfunction of HSCs.

中文翻译：

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组蛋白去甲基化酶LSD1调节造血干细胞体内稳态并通过内毒素休克保护其免于死亡

造血干细胞（HSC）在体内平衡过程中保持静止状态，但在急性感染中，它们退出静止状态以增加免疫细胞的产量，即所谓的“紧急造血”。然而，HSCs在败血性休克期间对严重感染的反应以及病理影响仍然难以阐明。在这里，我们报告说，组蛋白脱甲基酶KDM1A / LSD1，作为哺乳动物血细胞生成的关键调节剂，是内毒素休克期间对HSCs炎症反应的负调节剂，通常在急性细菌或病毒感染期间观察到。炎症引起的LSD1缺乏症会导致过度增殖和过度炎症性骨髓祖细胞的病理种群急剧增加，从而导致败血性休克表型和急性死亡。不料，LSD1。HSC中LSD1的抑制至少在很大程度上是由一群炎症诱导的microRNA引起的。重要的是，用表达这些炎症诱导的微RNA抑制剂的骨髓祖细胞重建小鼠，可以在急性LPS给药后体内抑制LSD1的表达，并防止内毒素性休克引起的死亡。我们的结果表明，LSD1激活剂或miRNA拮抗剂可以作为治疗威胁生命的败血症性休克的治疗方法，其特征是HSC功能异常。