Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis

• 成果类型: Article
• 署名作者: Gaertner, Florian; Ishikawa-Ankerhold, Hellen; Stutte, Susanne; Fu, Wenwen; Weitz, Jutta; Dueck, Anne; Nelakuditi, Bhavishya; Fumagalli, Valeria; van den Heuvel, Dominic; Belz, Larissa; Sobirova, Gulnoza; Zhang, Zhe; Titova, Anna; Navarro, Alejandro Martinez; Pekayvaz, Kami; Lorenz, Michael; von Baumgarten, Louisa; Kranich, Jan; Straub, Tobias; Popper, Bastian; Zheden, Vanessa; Kaufmann, Walter Anton; Guo, Chenglong; Piontek, Guido; von Stillfried, Saskia; Boor, Peter; Colonna, Marco; Clauss, Sebastian; Schulz, Christian; Brocker, Thomas; Walzog, Barbara; Scheiermann, Christoph; Aird, William C.; Nerlov, Claus; Stark, Konstantin; Petzold, Tobias; Engelhardt, Stefan; Sixt, Michael; Hauschild, Robert; Rudelius, Martina; Oostendorp, Robert A. J.; Iannacone, Matteo; Heinig, Matthias; Massberg, Steffen
• 署名单位: University of Munich; Institute of Science & Technology - Austria; German Centre for Cardiovascular Research; Munich Heart Alliance; University of Munich; University of Munich; University of Munich; Technical University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Technical University of Munich; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; Vita-Salute San Raffaele University; University of Munich; University of Munich; University of Munich; University of Munich; RWTH Aachen University; RWTH Aachen University Hospital; Washington University (WUSTL); University of Geneva; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; University of Oxford; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; German Centre for Cardiovascular Research; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Technical University of Munich
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6717
• DOI: 10.1038/s41586-024-07671-y
• 发表日期: 2024-07-18
• 页码: 645-+
• 关键词: hematopoietic stem-cells; megakaryocytes; platelets; macrophages; infection; bone; thrombocytopenia; immunity; distinct; mice

摘要

Platelet homeostasis is essential for vascular integrity and immune defence(1,2). 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 unclear(3,4). 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 IFN alpha 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 infection(5). 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. Plasmacytoid dendritic cells monitor the bone marrow for apoptotic megakaryocytes (MKs) and deliver IFN alpha to the MK niche, triggering local on-demand proliferation and maturation of MK progenitors.