Nature | 浆细胞样树突状细胞调控巨核细胞生成稳态

德国慕尼黑大学Florian Gaertner团队在Nature发表题为Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis的研究论文。研究人员揭示了浆细胞样树突状细胞（pDCs）通过监测骨髓中的凋亡巨核细胞（MKs）并释放干扰素α（IFNα），从而促进局部MK祖细胞的增殖和成熟，维持血小板和MKs生成在稳态和应激状态下的平衡。

pDCs是一种特殊的固有免疫细胞亚群，专门检测凋亡细胞和核酸，在骨髓中丰度较高。研究人员使用BDCA2-DTR小鼠模型和抗体阻断方法，发现pDCs的去除显著减少了骨髓中的MKs和MKPs数量，导致外周血小板数量下降。

pDCs可以感知MKs来源的细胞外DNA，通过MYD88-IRF7信号通路产生I型干扰素，维持骨髓中的IFNα水平，进而通过IFNAR信号促进MK祖细胞的扩增和成熟，维持稳态和应激下的血小板生成。

在人类骨髓样本中，pDC与MK的接触在稳态和血小板减少时显著增加，表明pDCs在MKs周转中起重要调控作用。由于pDCs是IFNα的主要来源，急性感染如COVID-19可以激活pDCs并释放过量IFNα，导致MKs异常增生。COVID-19患者和SARS-CoV-2感染小鼠的骨髓中pDCs数量和pDC与MK的接触显著增加，MKs增生也相应增加。阻断IFNα信号传导可以减少这种异常增生，提示严重感染可能干扰pDCs对MKs生成的正常调控。

这些研究不仅揭示了pDCs在调节MKs生成和血小板稳态中的重要作用，还为感染性疾病的治疗提供了新的视角。

Abstract

Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.